bims-senagi Biomed News
on Senescence and aging
Issue of 2022‒07‒17
eighty papers selected by
Maria Grazia Vizioli
Mayo Clinic

  1. Front Aging. 2022 ;3 866718
      The influence of the activation of a cellular phenotype termed senescence and it's importance in ageing and age-related diseases is becoming more and more evident. In fact, there is a huge effort to tackle these diseases via therapeutic drugs targeting senescent cells named senolytics. However, a clearer understanding of how senescence is activated and the influence it has on specific cellular types and tissues is needed. Here, we describe general triggers and characteristics of senescence. In addition, we describe the influence of senescent cells in ageing and different age-related diseases.
    Keywords:  SASP; age-related disease; ageing; extracellular vesicles; hallmarks; senescence; senolytics; senomorphics
  2. FEBS J. 2022 Jul 11.
      Cellular senescence is a state of irreversible cell cycle arrest that often emerges after tissue damage and in age-related diseases. Through the production of a multicomponent secretory phenotype (SASP), senescent cells can impact the regeneration and function of tissues. However, the effects of senescent cells and their SASP are very heterogeneous and depend on the tissue environment and type as well as the duration of injury, the degree of persistence of senescent cells, and the organism's age. While the transient presence of senescent cells is widely believed to be beneficial, recent data suggest that it is detrimental for tissue regeneration after acute damage. Further, although senescent cell persistence is typically associated with the progression of age-related chronic degenerative diseases, it now appears to be also necessary for correct tissue function in the elderly. Here, we discuss what is currently known about the roles of senescent cells and their SASP in tissue regeneration in aging and age-related diseases, highlighting their (negative and/or positive) contributions. We provide insight for future research, including the possibility of senolytic-based therapies and cellular reprogramming, with aims ranging from enhancing tissue repair to extending a healthy lifespan.
    Keywords:  SASP; Senescence; aging; disease; regeneration
  3. Nat Rev Immunol. 2022 Jul 13.
      Genomic instability is an important driver of ageing. The accumulation of DNA damage is believed to contribute to ageing by inducing cell death, senescence and tissue dysfunction. However, emerging evidence shows that inflammation is another major consequence of DNA damage. Inflammation is a hallmark of ageing and the driver of multiple age-related diseases. Here, we review the evidence linking DNA damage, inflammation and ageing, highlighting how premature ageing syndromes are associated with inflammation. We discuss the mechanisms by which DNA damage induces inflammation, such as through activation of the cGAS-STING axis and NF-κB activation by ATM. The triggers for activation of these signalling cascades are the age-related accumulation of DNA damage, activation of transposons, cellular senescence and the accumulation of persistent R-loops. We also discuss how epigenetic changes triggered by DNA damage can lead to inflammation and ageing via redistribution of heterochromatin factors. Finally, we discuss potential interventions against age-related inflammation.
  4. Front Aging. 2022 ;3 900028
      With aging, there is increased dysfunction of both innate and adaptive immune responses, which contributes to impaired immune responses to pathogens and greater mortality and morbidity. This age-related immune dysfunction is defined in general as immunosenescence and includes an increase in the number of memory T cells, loss of ability to respond to antigen and a lingering level of low-grade inflammation. However, certain features of immunosenescence are similar to cellular senescence, which is defined as the irreversible loss of proliferation in response to damage and stress. Importantly, senescence cells can develop an inflammatory senescence-associated secretory phenotype (SASP), that also drives non-autonomous cellular senescence and immune dysfunction. Interestingly, viral infection can increase the extent of immune senescence both directly and indirectly, leading to increased immune dysfunction and inflammation, especially in the elderly. This review focuses on age-related immune dysfunction, cellular senescence and the impaired immune response to pathogens.
    Keywords:  aging; immunity; immunosenescence; senescence; senolytic
  5. J Prev Alzheimers Dis. 2022 ;9(3): 523-531
      The underlying processes occurring in aging are complex, involving numerous biological changes that result in chronic cellular stress and sterile inflammation. One of the main hallmarks of aging is senescence. While originally the term senescence was defined in the field of oncology, further research has established that also microglia, astrocytes and neurons become senescent. Since age is the main risk factor for neurodegenerative diseases, it is reasonable to argue that cellular senescence might play a major role in Alzheimer's disease. Specific cellular changes seen during Alzheimer's disease are similar to those observed during senescence across all resident brain cell types. Furthermore, increased levels of senescence-associated secretory phenotype proteins such as IL-6, IGFBP, TGF-β and MMP-10 have been found in both CSF and plasma samples from Alzheimer's disease patients. In addition, genome-wide association studies have identified that individuals with Alzheimer's disease carry a high burden of genetic risk variants in genes known to be involved in senescence, including ADAM10, ADAMTS4, and BIN1. Thus, cellular senescence is emerging as a potential underlying disease process operating in Alzheimer's disease. This has also attracted more attention to exploiting cellular senescence as a therapeutic target. Several senolytic compounds with the capability to eliminate senescent cells have been examined in vivo and in vitro with notable results, suggesting they may provide a novel therapeutic avenue. Here, we reviewed the current knowledge of cellular senescence and discussed the evidence of senescence in various brain cell types and its putative role in inflammaging and neurodegenerative processes.
    Keywords:  Aging; Alzheimer’s disease; neuroinflammation; senescence; senescence-associated secretory phenotype
  6. STAR Protoc. 2022 Jul 11. pii: S2666-1667(22)00419-1. [Epub ahead of print]3(3): 101539
      Senescent cells accumulation is associated with aging and age-related diseases, and recent findings suggest that autophagy, the activity of the intracellular degradation system, decreases during senescence. In this protocol, we detail steps to induce cellular senescence in response to DNA damage, evaluate the senescent state using SA-β-gal staining and western blot for p21, LAMP1, and Lamin B1, and detect autophagy via LC3 western blotting. This protocol can be used in most cell lines and for various types of senescent cells. For complete details on the use and execution of this protocol, please refer to Yamamoto-Imoto et al. (2022).
    Keywords:  Cell Biology; Cell culture; Cell-based Assays
  7. Front Aging. 2022 ;3 828058
      Increasing chronological age is the greatest risk factor for human diseases. Cellular senescence (CS), which is characterized by permanent cell-cycle arrest, has recently emerged as a fundamental mechanism in developing aging-related pathologies. During the aging process, senescent cell accumulation results in senescence-associated secretory phenotype (SASP) which plays an essential role in tissue dysfunction. Although discovered very recently, senotherapeutic drugs have been already involved in clinical studies. This review gives a summary of the molecular mechanisms of CS and its role particularly in the development of cardiovascular diseases (CVD) as the leading cause of death. In addition, it addresses alternative research tools including the nonhuman and human models as well as computational techniques for the discovery of novel therapies. Finally, senotherapeutic approaches that are mainly classified as senolytics and senomorphics are discussed.
    Keywords:  Aging; Blind mole-rat; Cardiovascular Diseases; Cellular senescence; Microchip; Naked mole-rat; Organoid; Senotherapeutics
  8. Cell Rep. 2022 Jul 12. pii: S2211-1247(22)00872-5. [Epub ahead of print]40(2): 111074
      Cellular senescence is an irreversible growth arrest with a dynamic secretome, termed the senescence-associated secretory phenotype (SASP). Senescence is a cell-intrinsic barrier for reprogramming, whereas the SASP facilitates cell fate conversion in non-senescent cells. However, the mechanisms by which reprogramming-induced senescence regulates cell plasticity are not well understood. Here, we investigate how the heterogeneity of paracrine senescence impacts reprogramming. We show that senescence promotes in vitro reprogramming in a stress-dependent manner. Unbiased proteomics identifies a catalog of SASP factors involved in the cell fate conversion. Amphiregulin (AREG), frequently secreted by senescent cells, promotes in vitro reprogramming by accelerating proliferation and the mesenchymal-epithelial transition via EGFR signaling. AREG treatment diminishes the negative effect of donor age on reprogramming. Finally, AREG enhances in vivo reprogramming in skeletal muscle. Hence, various SASP factors can facilitate cellular plasticity to promote reprogramming and tissue repair.
    Keywords:  CP: Cell biology; EGFR; SASP; aging; amphiregulin; cellular plasticity; cellular senescence; in vitro reprogramming; in vivo reprogramming; muscle regeneration; quantitative proteomics
  9. Front Aging. 2021 ;2 797320
      Aging is a process leading to a progressive loss of physiological integrity and homeostasis, and a primary risk factor for many late-onset chronic diseases. The mechanisms underlying aging have long piqued the curiosity of scientists. However, the idea that aging is a biological process susceptible to genetic manipulation was not well established until the discovery that the inhibition of insulin/IGF-1 signaling extended the lifespan of C. elegans. Although aging is a complex multisystem process, López-Otín et al. described aging in reference to nine hallmarks of aging. These nine hallmarks include: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Due to recent advances in lipidomic, investigation into the role of lipids in biological aging has intensified, particularly the role of sphingolipids (SL). SLs are a diverse group of lipids originating from the Endoplasmic Reticulum (ER) and can be modified to create a vastly diverse group of bioactive metabolites that regulate almost every major cellular process, including cell cycle regulation, senescence, proliferation, and apoptosis. Although SL biology reaches all nine hallmarks of aging, its contribution to each hallmark is disproportionate. In this review, we will discuss in detail the major contributions of SLs to the hallmarks of aging and age-related diseases while also summarizing the importance of their other minor but integral contributions.
    Keywords:  age-related diseases; aging; ceramide; hallmarks of aging; lipids; sphingolipids
  10. Front Aging. 2021 ;2 821904
      Aging results in the progressive accumulation of senescent cells in tissues that display loss of proliferative capacity and acquire a senescence-associated secretory phenotype (SASP). The tumor suppressor, p16 INK4A , which slows the progression of the cell cycle, is highly expressed in most senescent cells and the removal of p16-expressing cells has been shown to be beneficial to tissue health. Although much work has been done to assess the effects of cellular senescence on a variety of different organs, little is known about the effects on skeletal muscle and whether reducing cellular senescent load would provide a therapeutic benefit against age-related muscle functional decline. We hypothesized that whole-body ablation of p16-expressing cells in the advanced stages of life in mice would provide a therapeutic benefit to skeletal muscle structure and function. Treatment of transgenic p16-3MR mice with ganciclovir (GCV) from 20 to 26 months of age resulted in reduced p16 mRNA levels in muscle. At 26 months of age, the masses of tibialis anterior, extensor digitorum longus, gastrocnemius and quadriceps muscles were significantly larger in GCV-treated compared with vehicle-treated mice, but this effect was limited to male mice. Maximum isometric force for gastrocnemius muscles was also greater in GCV-treated male mice compared to controls. Further examination of muscles of GCV- and vehicle-treated mice showed fewer CD68-positive macrophages present in the tissue following GCV treatment. Plasma cytokine levels were also measured with only one, granulocyte colony stimulating factor (G-CSF), out of 22 chemokines analyzed was reduced in GCV-treated mice. These findings show that genetic ablation of p16+ senescent cells provides moderate and sex specific therapeutic benefits to muscle mass and function.
    Keywords:  aging; inflammation; muscle atrophy; sarcopenia; senescence
  11. J Clin Invest. 2022 Jul 15. pii: e158448. [Epub ahead of print]132(14):
      Aging is characterized by the accumulation of damage to macromolecules and cell architecture that triggers a proinflammatory state in blood and solid tissues, termed inflammaging. Inflammaging has been implicated in the pathogenesis of many age-associated chronic diseases as well as loss of physical and cognitive function. The search for mechanisms that underlie inflammaging focused initially on the hallmarks of aging, but it is rapidly expanding in multiple directions. Here, we discuss the threads connecting cellular senescence and mitochondrial dysfunction to impaired mitophagy and DNA damage, which may act as a hub for inflammaging. We explore the emerging multi-omics efforts that aspire to define the complexity of inflammaging - and identify molecular signatures and novel targets for interventions aimed at counteracting excessive inflammation and its deleterious consequences while preserving the physiological immune response. Finally, we review the emerging evidence that inflammation is involved in brain aging and neurodegenerative diseases. Our goal is to broaden the research agenda for inflammaging with an eye on new therapeutic opportunities.
  12. Nucleic Acids Res. 2022 Jul 12. pii: gkac603. [Epub ahead of print]
      Cellular senescence triggers various types of heterochromatin remodeling that contribute to aging. However, the age-related mechanisms that lead to these epigenetic alterations remain elusive. Here, we asked how two key aging hallmarks, telomere shortening and constitutive heterochromatin loss, are mechanistically connected during senescence. We show that, at the onset of senescence, pericentromeric heterochromatin is specifically dismantled consisting of chromatin decondensation, accumulation of DNA breakages, illegitimate recombination and loss of DNA. This process is caused by telomere shortening or genotoxic stress by a sequence of events starting from TP53-dependent downregulation of the telomere protective protein TRF2. The resulting loss of TRF2 at pericentromeres triggers DNA breaks activating ATM, which in turn leads to heterochromatin decondensation by releasing KAP1 and Lamin B1, recombination and satellite DNA excision found in the cytosol associated with cGAS. This TP53-TRF2 axis activates the interferon response and the formation of chromosome rearrangements when the cells escape the senescent growth arrest. Overall, these results reveal the role of TP53 as pericentromeric disassembler and define the basic principles of how a TP53-dependent senescence inducer hierarchically leads to selective pericentromeric dismantling through the downregulation of TRF2.
  13. Front Pharmacol. 2022 ;13 912825
      Recent studies indicated that hepatocyte senescence plays an important role in the development of alcoholic fatty liver disease (AFLD), suggesting that inhibition of hepatocyte senescence might be a potential strategy for AFLD treatment. The present study investigated the effect of curcumol, a component from the root of Rhizoma Curcumae, on hepatocyte senescence in AFLD and the underlying mechanisms implicated. The results showed that curcumol was able to reduce lipid deposition and injury in livers of ethanol liquid diet-fed mice and in ethanol-treated LO2 cells. Both in vivo and in vitro studies indicated that supplementation with curcumol effectively alleviated ethanol-induced cellular senescence as manifested by a decrease in senescence-associated β-galactosidase (SA-β-gal) activity, a downregulated expression of senescence-related markers p16 and p21, and dysfunction of the telomere and telomerase system. Consistently, treatment with curcumol led to a marked suppression of ethanol-induced formation of cytoplasmic chromatin fragments (CCF) and subsequent activation of cGAS-STING, resulting in a significant reduction in senescence-associated secretory phenotype (SASP)-related inflammatory factors' secretion. Further studies indicated that curcumol's inhibition of CCF formation might be derived from blocking the interaction of LC3B with lamin B1 and maintaining nuclear membrane integrity. Taken together, these results indicated that curcumol was capable of ameliorating AFLD through inhibition of hepatocyte senescence, which might be attributed to its blocking of LC3B and lamin B1 interaction and subsequent inactivation of the CCF-cGAS-STING pathway. These findings suggest a promising use of curcumol in the treatment of AFLD.
    Keywords:  LC3B–lamin B1; alcoholic fatty liver disease; cellular senescence; curcumol; cytoplasmic chromatin fragments
  14. Cold Spring Harb Perspect Biol. 2022 Jul 11. pii: a041221. [Epub ahead of print]
      Cellular senescence, once thought an artifact of in vitro culture or passive outcome of aging, has emerged as fundamental to tissue development and function. The senescence mechanism importantly halts cell cycle progression to protect against tumor formation, while transiently present senescent cells produce a complex secretome (or SASP) of inflammatory mediators, proteases, and growth factors that guide developmental remodeling and tissue regeneration. Transiently present senescence is important for skin repair, where it accelerates extracellular matrix formation, limits fibrosis, promotes reepithelialization, and modulates inflammation. Unfortunately, advanced age and diabetes drive pathological accumulation of senescent cells in chronic wounds, which is perpetuated by a proinflammatory SASP, advanced glycation end-products, and oxidative damage. Although the biology of wound senescence remains incompletely understood, drugs that selectively target senescent cells are showing promise in clinical trials for diverse pathological conditions. It may not be long before senescence-targeted therapies will be available for the management, or perhaps even prevention, of chronic wounds.
  15. Front Aging. 2021 ;2 686382
      Cellular senescence, the irreversible growth arrest of cells from conditional renewal populations combined with a radical shift in their phenotype, is a hallmark of ageing in some mammalian species. In the light of this, interest in the detection of senescent cells in different tissues and different species is increasing. However much of the prior work in this area is heavily slanted towards studies conducted in humans and rodents; and in these species most studies concern primary fibroblasts or cancer cell lines rendered senescent through exposure to a variety of stressors. Complex techniques are now available for the detailed analysis of senescence in these systems. But, rather than focussing on these methods this review instead examines techniques for the simple and reproducible detection of senescent cells. Intended primary for the non-specialist who wishes to quickly detect senescent cells in tissues or species which may lack a significant evidence base on the phenomenon it emphasises the power of the original techniques used to demonstrate the senescence of cells, their interrelationship with other markers and their potential to inform on the senescent state in new species and archival specimens.
    Keywords:  ageing; detection; labelling index; lipofuscin; senescence
  16. Front Aging. 2021 ;2 714239
      As people around the world continue to live longer, maintaining a good quality of life is of increasing importance. The COVID-19 pandemic revealed that the elderly are disproportionally vulnerable to infectious diseases and Immunosenescence plays a critical role in that. An ageing immune system influences the conventional activity of T cells which are at the forefront of eliminating harmful foreign antigens. With ageing, unconventional end-stage T cells, that exhibit a senescent phenotype, amass. These senescent T cells deviate from T cell receptor (TCR) signaling toward natural killer (NK) activity. The transition toward innate immune cell function from these adaptor T cells impacts antigen specificity, contributing to increased susceptibility of infection in the elderly. The mechanism by which senescent T cells arise remains largely unclear however in this review we investigate the part that bystander activation plays in driving the change in function of T cells with age. Cytokine-induced bystander activation may offer a plausible explanation for the induction of NK-like activity and senescence in T cells. Further understanding of these specific NK-like senescent T cells allows us to identify the benefits and detriments of these cells in health and disease which can be utilized or regulated, respectively. This review discusses the dynamic of senescent T cells in adopting NK-like T cells and the implications that has in an infectious disease context, predominately in the elderly.
    Keywords:  NK-like CD8(+) T cells; ageing; bystander activation of T cells; immunosenecence; senescent T cells
  17. Front Aging. 2022 ;3 870489
      Chronic inflammation affects many diseases and conditions, including aging. Interferons are a part of the immune defense against viral infections. Paradoxically, various aging tissues and organs from mammalian hosts perpetually accumulate changes brought by interferon pathway activation. Herein, we connote the mechanisms behind this phenomenon and discuss its implications in age-related pathology.
    Keywords:  aging; inflammaging; interferon; laminopathy; mitochondria; senescence; transposable elements
  18. Mol Psychiatry. 2022 Jul 15.
      Aging is a major risk factor for a number of chronic diseases, including neurodegenerative and cerebrovascular disorders. Aging processes have therefore been discussed as potential targets for the development of novel and broadly effective preventatives or therapeutics for age-related diseases, including those affecting the brain. Mechanisms thought to contribute to aging have been summarized under the term the "hallmarks of aging" and include a loss of proteostasis, mitochondrial dysfunction, altered nutrient sensing, telomere attrition, genomic instability, cellular senescence, stem cell exhaustion, epigenetic alterations and altered intercellular communication. We here examine key claims about the "hallmarks of aging". Our analysis reveals important weaknesses that preclude strong and definitive conclusions concerning a possible role of these processes in shaping organismal aging rate. Significant ambiguity arises from the overreliance on lifespan as a proxy marker for aging, the use of models with unclear relevance for organismal aging, and the use of study designs that do not allow to properly estimate intervention effects on aging rate. We also discuss future research directions that should be taken to clarify if and to what extent putative aging regulators do in fact interact with aging. These include multidimensional analytical frameworks as well as designs that facilitate the proper assessment of intervention effects on aging rate.
  19. Front Aging. 2021 ;2 790702
      Aging is a physiological process defined by decreased cellular and tissue functions. Reduced capacity of protein degradation is one of the important hallmarks of aging that may lead to misfolded protein accumulation and progressive loss of function in organ systems. Recognition of unfolded/misfolded protein aggregates via endoplasmic reticulum (ER) stress sensors activates an adaptive mechanism, the unfolded protein response (UPR). The initial step of UPR is defined by chaperone enhancement, ribosomal translation suppression, and misfolded protein degradation, while prolonged ER stress triggers apoptosis. MicroRNAs (miRNAs) are non-coding RNAs affecting various signaling pathways through degradation or translational inhibition of targeted mRNAs. Therefore, UPR and miRNA impairment in aging and age-related diseases is implicated in various studies. This review will highlight the recent insights in ER stress-miRNAs alterations during aging and age-related diseases, including metabolic, cardiovascular, and neurodegenerative diseases and several cancers.
    Keywords:  aging; cancer; cardiovascular diseases; endoplasmic reticulum stress; metabolic disorders; microRNA; neurodegenerative diseases
  20. Front Aging. 2022 ;3 840827
      An optimal immune response requires the appropriate interaction between the innate and the adaptive arms of the immune system as well as a proper balance of activation and regulation. After decades of life, the aging immune system is continuously exposed to immune stressors and inflammatory assaults that lead to immune senescence. In this review, we will discuss inflammaging in the elderly, specifically concentrating on IL-6 and IL-1b in the context of T lymphocytes, and how inflammation is related to mortality and morbidities, specifically cardiovascular disease and cancer. Although a number of studies suggests that the anti-inflammatory cytokine TGF-b is elevated in the elderly, heightened inflammation persists. Thus, the regulation of the immune response and the ability to return the immune system to homeostasis is also important. Therefore, we will discuss cellular alterations in aging, concentrating on senescent T cells and CD4+ CD25+ FOXP3+ regulatory T cells (Tregs) in aging.
    Keywords:  dysregulated tregs; elderly; immune senescence; inflammaging; inflammation; t cell senescence
  21. Front Aging. 2020 ;1 602108
    Keywords:  aging immune system; cellular senescence; geroscience hypothesis; health span; inflammaging
  22. Trends Cancer. 2022 Jul 07. pii: S2405-8033(22)00135-2. [Epub ahead of print]
      Cancer is an age-related disease, as incidence and mortality for most types of cancer increase with age. However, how molecular alterations in tumors differ among patients of different ages remains poorly understood. Recent studies have shed light on the age-associated molecular landscapes in cancer. Here, we summarize the main findings of these current studies, highlighting major differences in the genomic, transcriptomic, epigenetic, and immunological landscapes between cancer in younger and older patients. Importantly, some cancer driver genes are mutated more frequently in younger or older patients. We discuss the potential roles of aging-related processes in shaping these age-related differences in cancer. We further emphasize the remaining unsolved questions that could provide important insights that will have implications in personalized medicine.
    Keywords:  aging; cancer genomics; cancer immune landscape; carcinoma; microenvironment
  23. Aging Cell. 2022 Jul 12. e13671
      The thymus is the primary immune organ responsible for generating self-tolerant and immunocompetent T cells. However, the thymus gradually involutes during early life resulting in declined naïve T-cell production, a process known as age-related thymic involution. Thymic involution has many negative impacts on immune function including reduced pathogen resistance, high autoimmunity incidence, and attenuated tumor immunosurveillance. Age-related thymic involution leads to a gradual reduction in thymic cellularity and thymic stromal microenvironment disruption, including loss of definite cortical-medullary junctions, reduction of cortical thymic epithelial cells and medullary thymic epithelial cells, fibroblast expansion, and an increase in perivascular space. The compromised thymic microenvironment in aged individuals substantially disturbs thymocyte development and differentiation. Age-related thymic involution is regulated by many transcription factors, micro RNAs, growth factors, cytokines, and other factors. In this review, we summarize the current understanding of age-related thymic involution mechanisms and effects.
    Keywords:  T cells; aging; thymic epithelial cells; thymic involution; thymus
  24. Signal Transduct Target Ther. 2022 Jul 11. 7(1): 231
      Aging-induced alternations of vasculature structures, phenotypes, and functions are key in the occurrence and development of vascular aging-related diseases. Multiple molecular and cellular events, such as oxidative stress, mitochondrial dysfunction, vascular inflammation, cellular senescence, and epigenetic alterations are highly associated with vascular aging physiopathology. Advances in nanoparticles and nanotechnology, which can realize sensitive diagnostic modalities, efficient medical treatment, and better prognosis as well as less adverse effects on non-target tissues, provide an amazing window in the field of vascular aging and related diseases. Throughout this review, we presented current knowledge on classification of nanoparticles and the relationship between vascular aging and related diseases. Importantly, we comprehensively summarized the potential of nanoparticles-based diagnostic and therapeutic techniques in vascular aging and related diseases, including cardiovascular diseases, cerebrovascular diseases, as well as chronic kidney diseases, and discussed the advantages and limitations of their clinical applications.
  25. Front Aging. 2021 ;2 783144
      The effects of short-term hyperoxia on age-related diseases and aging biomarkers have been reported in animal and human experiments using different protocols; however, the findings of the studies remain conflicting. In this systematic review, we summarized the existing reports in the effects of short-term hyperoxia on age-related diseases, hypoxia-inducible factor 1α (HIF-1α), and other oxygen-sensitive transcription factors relevant to aging, telomere length, cellular senescence, and its side effects. This review was done as described in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. A systematic search was done in PubMed, Google Scholar, and Cochrane Library and from the references of selected articles to identify relevant studies until May 2021. Of the total 1,699 identified studies, 17 were included in this review. Most of the studies have shown significant effects of short-term hyperoxia on age-related diseases and aging biomarkers. The findings of the studies suggest the potential benefits of short-term hyperoxia in several clinical applications such as for patients undergoing stressful operations, restoration of cognitive function, and the treatment of severe traumatic brain injury. Short-term hyperoxia has significant effects in upregulation or downregulation of transcription factors relevant to aging such as HIF-1α, nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-kB), and nuclear factor (erythroid-derived 2)-like 2 (NRF2) among others. Short-term hyperoxia also has significant effects to increase antioxidant enzymes, and increase telomere length and clearance of senescent cells. Some of the studies have also reported adverse consequences including mitochondrial DNA damage and nuclear cataract formation depending on the dose and duration of oxygen exposure. In conclusion, short-term hyperoxia could be a feasible treatment option to treat age-related disease and to slow aging because of its ability to increase antioxidant enzymes, significantly increase telomere length and clearance of senescent cells, and improve cognitive function, among others. The reported side effects of hyperoxia vary depending on the dose and duration of exposure. Therefore, it seems that additional studies for better understanding the beneficial effects of short-term hyperoxia and for minimizing side effects are necessary for optimal clinical application.
    Keywords:  age-related diseases; aging; aging biomarkers; effects; hyperoxia
  26. Theranostics. 2022 ;12(11): 5237-5257
      Rationale: Aging in the heart is a gradual process, involving continuous changes in cardiovascular cells, including cardiomyocytes (CMs), namely cellular senescence. These changes finally lead to adverse organ remodeling and resulting in heart failure. This study exploits CMs from human induced pluripotent stem cells (iCMs) as a tool to model and characterize mechanisms involved in aging. Methods and Results: Human somatic cells were reprogrammed into human induced pluripotent stem cells and subsequently differentiated in iCMs. A senescent-like phenotype (SenCMs) was induced by short exposure (3 hours) to doxorubicin (Dox) at the sub-lethal concentration of 0.2 µM. Dox treatment induced expression of cyclin-dependent kinase inhibitors p21 and p16, and increased positivity to senescence-associated beta-galactosidase when compared to untreated iCMs. SenCMs showed increased oxidative stress, alteration in mitochondrial morphology and depolarized mitochondrial membrane potential, which resulted in decreased ATP production. Functionally, when compared to iCMs, SenCMs showed, prolonged multicellular QTc and single cell APD, with increased APD variability and delayed afterdepolarizations (DADs) incidence, two well-known arrhythmogenic indexes. These effects were largely ascribable to augmented late sodium current (INaL) and reduced delayed rectifier potassium current (Ikr). Moreover sarcoplasmic reticulum (SR) Ca2+ content was reduced because of downregulated SERCA2 and increased RyR2-mediated Ca2+ leak. Electrical and intracellular Ca2+ alterations were mostly justified by increased CaMKII activity in SenCMs. Finally, SenCMs phenotype was furtherly confirmed by analyzing physiological aging in CMs isolated from old mice in comparison to young ones. Conclusions: Overall, we showed that SenCMs recapitulate the phenotype of aged primary CMs in terms of senescence markers, electrical and Ca2+ handling properties and metabolic features. Thus, Dox-induced SenCMs can be considered a novel in vitro platform to study aging mechanisms and to envision cardiac specific anti-aging approach in humans.
    Keywords:  Induced pluripotent stem cell-derived cardiomyocytes; aging; heart; senescence
  27. Mol Neurobiol. 2022 Jul 14.
      The mitochondrial theory of aging is characterized by mitochondrial electron transport chain dysfunction. As a hallmark of aging, an increasing number of investigations have attempted to improve mitochondrial function in both aging and age-related disease. Emerging from these attempts, methods involving mitochondrial isolation, transfusion, and transplantation have taken center stage. In particular, mitochondrial transfusion refers to the administration of mitochondria from healthy tissue into the bloodstream or into tissues affected by injury, disease, or aging. In this study, methods of mitochondrial isolation and transfusion were developed and utilized. First, we found a significant decrease (p < 0.05) in the expression of mitochondrial complex proteins (I-V) in aged (12 months old) mouse brain tissue (C57BL/6 mice) in comparison to healthy young brain tissue (1 month old). To investigate whether healthy young mitochondria taken from the liver could improve mitochondrial function in older animals, we intravenously injected mitochondria isolated from young C57BL/6 mice into aged mice from the same strain. This study, for the first time, demonstrates that mitochondrial transfusion significantly (p < 0.05) improves mitochondrial function via the up-regulation of the mitochondrial complex II protein subunit SDHB in the hippocampus of aged mice. This result has identified a role for mitochondrial complex II in the aging process. Therefore, mitochondrial complex II could serve as a putative target for therapeutic interventions against aging. However, more importantly, methods of mitochondrial transfusion should be further tested to treat a variety of human diseases or disorders and to slow down or reverse processes of aging.
    Keywords:  Age-related disease; Aging; Bioenergetics; Brain; Complex II; Mitochondrial dysfunction; Mitochondrial transfusion; Neuroscience
  28. Front Aging. 2022 ;3 820215
      The risk of morbidity and mortality increases exponentially with age. Chronic inflammation, accumulation of DNA damage, dysfunctional mitochondria, and increased senescent cell load are factors contributing to this. Mechanistic investigations have revealed specific pathways and processes which, proposedly, cause age-related phenotypes such as frailty, reduced physical resilience, and multi-morbidity. Among promising treatments alleviating the consequences of aging are caloric restriction and pharmacologically targeting longevity pathways such as the mechanistic target of rapamycin (mTOR), sirtuins, and anti-apoptotic pathways in senescent cells. Regulation of these pathways and processes has revealed significant health- and lifespan extending results in animal models. Nevertheless, it remains unclear if similar results translate to humans. A requirement of translation are the development of age- and morbidity associated biomarkers as longitudinal trials are difficult and not feasible, practical, nor ethical when human life span is the endpoint. Current biomarkers and the results of anti-aging intervention studies in humans will be covered within this paper. The future of clinical trials targeting aging may be phase 2 and 3 studies with larger populations if safety and tolerability of investigated medication continues not to be a hurdle for further investigations.
    Keywords:  NAD; aging; caloric restriction; clinical trials; exercise; rapamycin
  29. Food Funct. 2022 Jul 11.
      Aging is a natural process accompanied by inflammation and oxidative stress and is closely associated with age-related diseases. As a direct precursor of glutathione, γ-glutamylcysteine (γ-GC) possesses antioxidant and anti-inflammatory properties; however, whether γ-GC plays an important role in anti-aging remains unknown. Here, we investigated the protective effects and mechanisms of γ-GC in D-galactose (D-gal)-induced senescence in PC12 cells and aging mice. Our results showed that γ-GC treatment significantly reduced the percentage of senescence-associated-β-galactosidase (SA-β-Gal)-positive cells and inhibited D-gal-induced cell cycle arrest in PC12 cells. The results of Nissl and hematoxylin and eosin (H&E) staining in mouse brain showed that γ-GC treatment markedly reversed the damage in the hippocampus of D-gal-induced aging mice. Moreover, γ-GC increased the phosphorylation of AMP-activated protein kinase (AMPK) to promote the nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) while inhibiting the nuclear translocation of deleted in breast cancer 1 (DBC1), which leads to the activation of sirtuin 1 (SIRT1) and deacetylation of p53 in the nucleus. Therefore, γ-GC may be a potential therapeutic candidate compound for the prevention and treatment of age-related diseases.
  30. Front Aging. 2021 ;2 797562
      Senescence in the cerebral endothelium has been proposed as a mechanism that can drive dysfunction of the cerebral vasculature, which precedes vascular dementia. Cysteine-rich angiogenic inducer 61 (Cyr61/CCN1) is a matricellular protein secreted by cerebral endothelial cells (CEC). CCN1 induces senescence in fibroblasts. However, whether CCN1 contributes to senescence in CEC and how this is regulated requires further study. Aging has been associated with the formation of four-stranded Guanine-quadruplexes (G4s) in G-rich motifs of DNA and RNA. Stabilization of the G4 structures regulates transcription and translation either by upregulation or downregulation depending on the gene target. Previously, we showed that aged mice treated with a G4-stabilizing compound had enhanced senescence-associated (SA) phenotypes in their brains, and these mice exhibited enhanced cognitive deficits. A sequence in the 3'-UTR of the human CCN1 mRNA has the ability to fold into G4s in vitro. We hypothesize that G4 stabilization regulates CCN1 in cultured primary CEC and induces endothelial senescence. We used cerebral microvessel fractions and cultured primary CEC from young (4-months old, m/o) and aged (18-m/o) mice to determine CCN1 levels. SA phenotypes were determined by high-resolution fluorescence microscopy in cultured primary CEC, and we used Thioflavin T to recognize RNA-G4s for fluorescence spectra. We found that cultured CEC from aged mice exhibited enhanced levels of SA phenotypes, and higher levels of CCN1 and G4 stabilization. In cultured CEC, CCN1 induced SA phenotypes, such as SA β-galactosidase activity, and double-strand DNA damage. Furthermore, CCN1 levels were upregulated by a G4 ligand, and a G-rich motif in the 3'-UTR of the Ccn1 mRNA was folded into a G4. In conclusion, we demonstrate that CCN1 can induce senescence in cultured primary CEC, and we provide evidence that G4 stabilization is a novel mechanism regulating the SASP component CCN1.
    Keywords:  CCN1; G-quadruplex; aging; endothelial cells; senescence
  31. Front Aging. 2022 ;3 854157
      Protein homeostasis (proteostasis) is maintained by a tightly regulated and interconnected network of biological pathways, preventing the accumulation and aggregation of damaged or misfolded proteins. Thus, the proteostasis network is essential to ensure organism longevity and health, while proteostasis failure contributes to the development of aging and age-related diseases that involve protein aggregation. The model organism Caenorhabditis elegans has proved invaluable for the study of proteostasis in the context of aging, longevity and disease, with a number of pivotal discoveries attributable to the use of this organism. In this review, we discuss prominent findings from C. elegans across the many key aspects of the proteostasis network, within the context of aging and disease. These studies collectively highlight numerous promising therapeutic targets, which may 1 day facilitate the development of interventions to delay aging and prevent age-associated diseases.
    Keywords:  C. elegans; autophagy; chaperones; protein aggragation; protein translation; proteostasis; stress responses; ubiquitin-proteasome system
  32. Ageing Res Rev. 2022 Jul 09. pii: S1568-1637(22)00125-8. [Epub ahead of print]80 101683
      Ovarian aging occurs approximately 10 years prior to the natural age-associated functional decline of other organ systems. With the increase of life expectancy worldwide, ovarian aging has gradually become a key health problem among women. Therefore, understanding the causes and molecular mechanisms of ovarian aging is very essential for the inhibition of age-related diseases and the promotion of health and longevity in women. Recently, studies have revealed an association between adipose tissue (AT) and ovarian aging. Alterations in the function and quantity of AT have profound consequences on ovarian function because AT is central for follicular development, lipid metabolism, and hormonal regulation. Moreover, the interplay between AT and the ovary is bidirectional, with ovary-derived signals directly affecting AT biology. In this review, we summarize the current knowledge of the complex molecular mechanisms controlling the crosstalk between the AT and ovarian aging, and further discuss how therapeutic targeting of the AT can delay ovarian aging.
    Keywords:  Adipose tissue; Obesity; Ovarian aging; Potential mechanism; Protective strategies
  33. Front Aging. 2021 ;2 681428
      Mitochondrial health and cellular metabolism can heavily influence the onset of senescence in T cells. CD8+ EMRA T cells exhibit mitochondrial dysfunction and alterations to oxidative phosphorylation, however, the metabolic properties of senescent CD8+ T cells from people living with type 2 diabetes (T2D) are not known. We show here that mitochondria from T2D CD8+ T cells had a higher oxidative capacity together with increased levels of mitochondrial reactive oxgen species (mtROS), compared to age-matched control cells. While fatty acid uptake was increased, fatty acid oxidation was impaired in T2D CD8+ EMRA T cells, which also showed an accumulation of lipid droplets and decreased AMPK activity. Increasing glucose and fatty acids in healthy CD8+ T cells resulted in increased p-p53 expression and a fragmented mitochondrial morphology, similar to that observed in T2D CD8+ EMRA T cells. The resulting mitochondrial changes are likely to have a profound effect on T cell function. Consequently, a better understanding of these metabolic abnormalities is crucial as metabolic manipulation of these cells may restore correct T cell function and help reduce the impact of T cell dysfunction in T2D.
    Keywords:  T cell; ageing; inflammation; metabolism; mitochondria; senescence; type 2 diabetes
  34. Front Aging. 2021 ;2 741843
      Discovering compounds that promote health during aging ("geroprotectors") is key to the retardation of age-related pathologies and the prevention of chronic age-related diseases. In in-silico and model organisms' lifespan screens, chondroitin sulfate has emerged as a geroprotective compound. Chondroitin sulfate is a glycosaminoglycan attached to extracellular matrix proteins and is naturally produced by our body. Oral supplementation of chondroitin sulfate shows a high tolerance in humans, preferable pharmacokinetics, a positive correlation with healthy human longevity, and efficacy in deceleration of age-related diseases in randomized clinical trials. We have recently shown that chondroitin sulfate supplementation increases the lifespan of C. elegans. Thus, chondroitin sulfate holds the potential to become a geroprotective strategy to promote health during human aging. This review discusses the two major potential mechanisms of action, extracellular matrix homeostasis and inhibition of inflammation, that counteract age-related pathologies upon chondroitin sulfate supplementation.
    Keywords:  anti inflammatory; chondroitin sulfate; drug discovery; extracellar matrix; healthy aging; longevity; matreotype; supplement
  35. Aging Cell. 2022 Jul 10. e13667
      Dysfunctional adipocyte precursors have emerged as key determinants for obesity- and aging-related inflammation, but the mechanistic basis remains poorly understood. Here, we explored the dysfunctional adipose tissue of elderly and obese individuals focusing on the metabolic and inflammatory state of human adipose-derived mesenchymal stromal cells (hASCs), and on sirtuins, which link metabolism and inflammation. Both obesity and aging impaired the differentiation potential of hASCs but had a different impact on their proliferative capacity. hASCs from elderly individuals (≥65 years) showed an upregulation of glycolysis-related genes, which was accompanied by increased lactate secretion and glycogen storage, a phenotype that was exaggerated by obesity. Multiplex protein profiling revealed that the metabolic switch to glycogenesis was associated with a pro-inflammatory secretome concomitant with a decrease in the protein expression of SIRT1 and SIRT6. siRNA-mediated knockdown of SIRT1 and SIRT6 in hASCs from lean adults increased the expression of pro-inflammatory and glycolysis-related markers, and enforced glycogen deposition by overexpression of protein targeting to glycogen (PTG) led to a downregulation of SIRT1/6 protein levels, mimicking the inflammatory state of hASCs from elderly subjects. Overall, our data point to a glycogen-SIRT1/6 signaling axis as a driver of age-related inflammation in adipocyte precursors.
    Keywords:  Aging; SIRT1; SIRT6; adipose-derived mesenchymal stromal cells; glycogen; glycolysis; inflammation; obesity
  36. Front Aging. 2022 ;3 867950
      The aging process causes profound restructuring of the host immune system, typically associated with declining host protection against cancer and infection. In the case of T cells, aging leads to the accumulation of a diverse set of T-cell aging-associated phenotypes (TASP), some of which have been implicated in driving tissue inflammation in autoimmune diseases. T cell aging as a risk determinant for autoimmunity is exemplified in two classical autoimmune conditions: rheumatoid arthritis (RA), a disease predominantly affecting postmenopausal women, and giant cell arteritis (GCA), an inflammatory vasculopathy exclusively occurring during the 6th-9th decade of life. Pathogenic T cells in RA emerge as a consequence of premature immune aging. They have shortening and fragility of telomeric DNA ends and instability of mitochondrial DNA. As a result, they produce a distinct profile of metabolites, disproportionally expand their endoplasmic reticulum (ER) membranes and release excess amounts of pro-inflammatory effector cytokines. Characteristically, they are tissue invasive, activate the inflammasome and die a pyroptotic death. Patients with GCA expand pathogenic CD4+ T cells due to aberrant expression of the co-stimulatory receptor NOTCH1 and the failure of the PD-1/PD-L1 immune checkpoint. In addition, GCA patients lose anti-inflammatory Treg cells, promoting tissue-destructive granulomatous vasculitis. In summary, emerging data identify T cell aging as a risk factor for autoimmune disease and directly link TASPs to the breakdown of T cell tolerance and T-cell-induced tissue inflammation.
    Keywords:  autoimmune disease; giant cell arteritis; immune aging; mitochondrial metabolism; rheumatoid arthritis; tissue invasiveness; treg aging; vasculitis
  37. Mol Psychiatry. 2022 Jul 15.
      Aging is characterized with a progressive decline in many cognitive functions, including behavioral flexibility, an important ability to respond appropriately to changing environmental contingencies. However, the underlying mechanisms of impaired behavioral flexibility in aging are not clear. In this study, we reported that necroptosis-induced reduction of neuronal activity in the basolateral amygdala (BLA) plays an important role in behavioral inflexibility in 5-month-old mice of the senescence-accelerated mice prone-8 (SAMP8) line, a well-established model with age-related phenotypes. Application of Nec-1s, a specific inhibitor of necroptosis, reversed the impairment of behavioral flexibility in SAMP8 mice. We further observed that the loss of glycogen synthase kinase 3α (GSK-3α) was strongly correlated with necroptosis in the BLA of aged mice and the amygdala of aged cynomolgus monkeys (Macaca fascicularis). Moreover, genetic deletion or knockdown of GSK-3α led to the activation of necroptosis and impaired behavioral flexibility in wild-type mice, while the restoration of GSK-3α expression in the BLA arrested necroptosis and behavioral inflexibility in aged mice. We further observed that GSK-3α loss resulted in the activation of mTORC1 signaling to promote RIPK3-dependent necroptosis. Importantly, we discovered that social isolation, a prevalent phenomenon in aged people, facilitated necroptosis and behavioral inflexibility in 4-month-old SAMP8 mice. Overall, our study not only revealed the molecular mechanisms of the dysfunction of behavioral flexibility in aged people but also identified a critical lifestyle risk factor and a possible intervention strategy.
  38. Front Aging. 2021 ;2 761333
      The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a master regulator of metabolism and aging. A complex signaling network converges on mTORC1 and integrates growth factor, nutrient and stress signals. Aging is a dynamic process characterized by declining cellular survival, renewal, and fertility. Stressors elicited by aging hallmarks such as mitochondrial malfunction, loss of proteostasis, genomic instability and telomere shortening impinge on mTORC1 thereby contributing to age-related processes. Stress granules (SGs) constitute a cytoplasmic non-membranous compartment formed by RNA-protein aggregates, which control RNA metabolism, signaling, and survival under stress. Increasing evidence reveals complex crosstalk between the mTORC1 network and SGs. In this review, we cover stressors elicited by aging hallmarks that impinge on mTORC1 and SGs. We discuss their interplay, and we highlight possible links in the context of aging and age-related diseases.
    Keywords:  MTOR; aging hallmarks; amino acids; autophagy; cellular signaling; insulin; stress; stress granules (SGs)
  39. Front Aging. 2021 ;2 708680
      Intervening in aging processes is hypothesized to extend healthy years of life and treat age-related disease, thereby providing great benefit to society. However, the ability to measure the biological aging process in individuals, which is necessary to test for efficacy of these interventions, remains largely inaccessible to the general public. Here we used NHANES physical activity accelerometer data from a wearable device and machine-learning algorithms to derive biological age predictions for individuals based on their movement patterns. We found that accelerated biological aging from our "MoveAge" predictor is associated with higher all-cause mortality. We further searched for nutritional or pharmacological compounds that associate with decelerated aging according to our model. A number of nutritional components peak in their association to decelerated aging later in life, including fiber, magnesium, and vitamin E. We additionally identified one FDA-approved drug associated with decelerated biological aging: the alpha-blocker doxazosin. We show that doxazosin extends healthspan and lifespan in C. elegans. Our work demonstrates how a biological aging score based on relative mobility can be accessible to the wider public and can potentially be used to identify and determine efficacy of geroprotective interventions.
    Keywords:  NHANES; aging; biological age; doxazosin; machine learning; wearable device
  40. Mech Ageing Dev. 2022 Jul 12. pii: S0047-6374(22)00089-6. [Epub ahead of print] 111707
      Aging is characterized by a progressive loss of tissue and organ function due to genetic and environmental factors, nutrition, and lifestyle. Oxidative stress is one the most important mechanisms of cellular senescence and increased frailty, resulting in several age-linked, noncommunicable diseases. Contributing events include genomic instability, telomere shortening, epigenetic mechanisms, reduced proteome homeostasis, altered stem-cell function, defective intercellular communication, progressive deregulation of nutrient sensing, mitochondrial dysfunction, and metabolic unbalance. These complex events and their interplay can be modulated by dietary habits and the ageing process, acting as potential measures of primary and secondary prevention. Promising nutritional approaches include the Mediterranean diet, the intake of dietary antioxidants, and the restriction of caloric intake. A comprehensive understanding of the ageing processes should promote new biomarkers of risk or diagnosis, but also beneficial treatments oriented to increase lifespan.
    Keywords:  Ageing; Nutrition; antioxidants; environmental factors; oxidative stress
  41. Front Aging. 2021 ;2 665637
      CD8+ T cells play an important role in protection against viral infections. With age, changes in the T-cell pool occur, leading to diminished responses against both new and recurring infections in older adults. This is thought to be due to a decrease in both T-cell numbers and T-cell receptor (TCR) diversity. Latent infection with cytomegalovirus (CMV) is assumed to contribute to this age-associated decline of the immune system. The observation that the level of TCR diversity in the total memory T-cell pool stays relatively stable during aging is remarkable in light of the constant input of new antigen-specific memory T cells. What happens with the diversity of the individual antigen-specific T-cell repertoires in the memory pool remains largely unknown. Here we studied the effect of aging on the phenotype and repertoire diversity of CMV-specific and Epstein-Barr virus (EBV)-specific CD8+ T cells, as well as the separate effects of aging and CMV-infection on the EBV-specific T-cell repertoire. Antigen-specific T cells against both persistent viruses showed an age-related increase in the expression of markers associated with a more differentiated phenotype, including KLRG-1, an increase in the fraction of terminally differentiated T cells, and a decrease in the diversity of the T-cell repertoire. Not only age, but also CMV infection was associated with a decreased diversity of the EBV-specific T-cell repertoire. This suggests that both CMV infection and age can impact the T-cell repertoire against other antigens.
    Keywords:  Epstein-Barr virus; T cell; T-cell repertoire; aging; cytomegalovirus
  42. Commun Biol. 2022 Jul 14. 5(1): 702
      The multifaceted nature of senescent cell cycle arrest necessitates the targeting of multiple factors arresting or promoting the cell cycle. We report that co-inhibition of ATM and ROCK by KU-60019 and Y-27632, respectively, synergistically increases the proliferation of human diploid fibroblasts undergoing replicative senescence through activation of the transcription factors E2F1 and FOXM1. Time-course transcriptome analysis identified FOXM1 and E2F1 as crucial factors promoting proliferation. Co-inhibition of the kinases ATM and ROCK first promotes the G2/M transition via FOXM1 activation, leading to accumulation of cells undergoing the G1/S transition via E2F1 activation. The combination of both inhibitors increased this effect more significantly than either inhibitor alone, suggesting synergism. Our results demonstrate a FOXM1- and E2F1-mediated molecular pathway enhancing cell cycle progression in cells with proliferative potential under replicative senescence conditions, and treatment with the inhibitors can be tested for senomorphic effect in vivo.
  43. Front Aging. 2022 ;3 837575
      Aging increases susceptibility to and severity of a variety of chronic and infectious diseases. Underlying this is dysfunction of the immune system, including chronic increases in low-grade inflammation (inflammaging) and age-related immunosuppression (immunosenescence). Growth differentiation factor-15 (GDF-15) is a stress-, infection-, and inflammation-induced cytokine which is increased in aging and suppresses immune responses. This mini review briefly covers existing knowledge on the immunoregulatory and anti-inflammatory roles of GDF-15, as well as its potential importance in aging and immune function.
    Keywords:  GDF-15; aging; immunity; immunosenescence; inflammaging
  44. Front Aging. 2022 ;3 905261
      Age-associated diseases represent a growing burden for global health systems in our aging society. Consequently, we urgently need innovative strategies to counteract these pathological disturbances. Overwhelming generation of reactive oxygen species (ROS) is associated with age-related damage, leading to cellular dysfunction and, ultimately, diseases. However, low-dose ROS act as crucial signaling molecules and inducers of a vaccination-like response to boost antioxidant defense mechanisms, known as mitohormesis. Consequently, modulation of ROS homeostasis by nutrition, exercise, or pharmacological interventions is critical in aging. Numerous nutrients and approved drugs exhibit pleiotropic effects on ROS homeostasis. In the current review, we provide an overview of drugs affecting ROS generation and ROS detoxification and evaluate the potential of these effects to counteract the development and progression of age-related diseases. In case of inflammation-related dysfunctions, cardiovascular- and neurodegenerative diseases, it might be essential to strengthen antioxidant defense mechanisms in advance by low ROS level rises to boost the individual ROS defense mechanisms. In contrast, induction of overwhelming ROS production might be helpful to fight pathogens and kill cancer cells. While we outline the potential of ROS manipulation to counteract age-related dysfunction and diseases, we also raise the question about the proper intervention time and dosage.
    Keywords:  Aging; Mitohormesis; Pharmacology; Reactive Oxygen Species; drugs; pleiotropy
  45. Exp Gerontol. 2022 Jul 07. pii: S0531-5565(22)00197-8. [Epub ahead of print]166 111889
      The regulation of mitochondrial turnover under conditions of stress occurs partly through the AMPK-NAD+-PGC1α-SIRT1 signalling pathway. This pathway can be affected by both genomic instability and chronic inflammation since these will result in an increased rate of NAD+ degradation through PARP1 and CD38 respectively. In this work we develop a computational model of this signalling pathway, calibrating and validating it against experimental data. The computational model is used to study mitochondrial turnover under conditions of stress and how it is affected by genomic instability, chronic inflammation and biological ageing in general. We report that the AMPK-NAD+-PGC1α-SIRT1 signalling pathway becomes less responsive with age and that this can prime for the accumulation of dysfunctional mitochondria.
    Keywords:  Cell Signalling; DNA damage; Mito-nuclear communication; Mitochondria; NAD; Systems modelling
  46. Front Aging. 2020 ;1 608076
      The metazoan genome composes of sets of housekeeping genes (HG) for fundamental cellular autonomous processes and integrative genes (IntG) that provide integrative functions and form the body as an integrated whole. The main paradigm for multicellularity development which has been improved in evolution, is the submission of the cellular autonomy to the interests of the integrated whole. Permanent increase of the "functional tax" of IntG-genome (IntG-shift) and epigenetic restriction of autonomy in phylogenesis/ontogenesis is the essence and root cause of aging, inherent in the very nature of highly integrated multicellularity. The regulation of the balance shift toward HG can be managed to eliminate aging and avoid carcinogenesis, which is only due to the irreversibility of this shift. Here we propose the criterion for measuring the functional and biological age of cells and the body as a whole for assessing the effectiveness of any type of palliative geroprotective or radical anti-aging intervention.
    Keywords:  aging; carcinogenesis; epigenetic; housekeeping genes; integrative genes; multicellularity; rejuvenation; senescence
  47. Front Aging. 2021 ;2 748591
      During the last 2 years, the entire world has been severely devastated by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic (COVID-19) as it resulted in several million deaths across the globe. While the virus infects people indiscriminately, the casualty risk is higher mainly in old, and middle-aged COVID-19 patients. The incidences of COVID-19 associated co-morbidity and mortality have a great deal of correlation with the weakened and malfunctioning immune systems of elderly people. Presumably, due to the physiological changes associated with aging and because of possible comorbidities such as diabetes, hypertension, obesity, cardiovascular, and lung diseases, which are more common in elderly people, may be considered as the reason making the elderly vulnerable to the infection on one hand, and COVID-19 associated complications on the other. The accretion of senescent immune cells not only contributes to the deterioration of host defense, but also results in elevated inflammatory phenotype persuaded immune dysfunction. In the present review, we envisage to correlate functioning of the immune defense of older COVID-19 patients with secondary/super infection, increased susceptibility or aggravation against already existing cancer, infectious, autoimmune, and other chronic inflammatory diseases. Moreover, we have discussed how age-linked modulations in the immune system affect therapeutic response against administered drugs as well as immunological response to various prophylactic measures including vaccination in the elderly host. The present review also provides an insight into the intricate pathophysiology of the aging and the overall immune response of the host to SARS-CoV-2 infection. A better understanding of age-related immune dysfunction is likely to help us in the development of targeted preemptive strategies for deadly COVID-19 in elderly patients.
    Keywords:  COVID-19; SARS-CoV-2; comorbidities; immunosenescence; inflammaging; innate and adaptive immune system
  48. Oxid Med Cell Longev. 2022 ;2022 3087916
      Aging is an inevitable consequence of life, and during this process, the epigenetic landscape changes and reactive oxygen species (ROS) accumulation increases. Inevitably, these changes are common in many age-related diseases, including neurodegeneration, hypertension, and cardiovascular diseases. In the current research, histone deacetylation 4 (HDAC4) was studied as a potential therapeutic target in vascular senescence. HDAC4 is a specific class II histone deacetylation protein that participates in epigenetic modifications and deacetylation of heat shock proteins and various transcription factors. There is increasing evidence to support that HDAC4 is a potential therapeutic target, and developments in the synthesis and testing of HDAC4 inhibitors are now gaining interest from academia and the pharmaceutical industry.
  49. Front Aging. 2021 ;2 727604
      Increasing scientific interest has been directed to sex as a biological and decisive factor on several diseases. Several different mechanisms orchestrate vascular function, as well as vascular dysfunction in cardiovascular and metabolic diseases in males and females. Certain vascular sex differences are present throughout life, while others are more evident before the menopause, suggesting two important and correlated drivers: genetic and hormonal factors. With the increasing life expectancy and aging population, studies on aging-related diseases and aging-related physiological changes have steeply grown and, with them, the use of aging animal models. Mouse and rat models of aging, the most studied laboratory animals in aging research, exhibit sex differences in many systems and physiological functions, as well as sex differences in the aging process and aging-associated cardiovascular changes. In the present review, we introduce the most common aging and senescence-accelerated animal models and emphasize that sex is a biological variable that should be considered in aging studies. Sex differences in the cardiovascular system, with a focus on sex differences in aging-associated vascular alterations (endothelial dysfunction, remodeling and oxidative and inflammatory processes) in these animal models are reviewed and discussed.
    Keywords:  aging; sex difference; vascular aging; vascular dysfunction; vascular senescence
  50. Front Aging. 2021 ;2 785171
      Telomeres are specialized nucleoprotein structures that form protective caps at the ends of chromosomes. Short telomeres are a hallmark of aging and a principal defining feature of short telomere syndromes, including dyskeratosis congenita (DC). Emerging evidence suggests a crucial role for critically short telomere-induced DNA damage signaling and mitochondrial dysfunction in cellular dysfunction in DC. A prominent factor linking nuclear DNA damage and mitochondrial homeostasis is the nicotinamide adenine dinucleotide (NAD) metabolite. Recent studies have demonstrated that patients with DC and murine models with critically short telomeres exhibit lower NAD levels, and an imbalance in the NAD metabolome, including elevated CD38 NADase and reduced poly (ADP-ribose) polymerase and SIRT1 activities. CD38 inhibition and/or supplementation with NAD precursors reequilibrate imbalanced NAD metabolism and alleviate mitochondrial impairment, telomere DNA damage, telomere dysfunction-induced DNA damage signaling, and cellular growth retardation in primary fibroblasts derived from DC patients. Boosting NAD levels also ameliorate chemical-induced liver fibrosis in murine models of telomere dysfunction. These findings underscore the relevance of NAD dysregulation to telomeropathies and demonstrate how NAD interventions may prove to be effective in combating cellular and organismal defects that occur in short telomere syndromes.
    Keywords:  CD38 NADase; DNA damage response; NAD metabolism; PARPs; SIRT1; mitochondrial dysfunction; short telomere syndromes; telomerase null mice
  51. Front Aging. 2021 ;2 773795
      Lipids are involved in a broad spectrum of canonical biological functions, from energy supply and storage by triacylglycerols to membrane formation by sphingolipids, phospholipids and glycolipids. Because of this wide range of functions, there is an overlap between age-associated processes and lipid pathways. Lipidome analysis revealed age-related changes in the lipid composition of various tissues in mice and humans, which were also influenced by diet and gender. Some changes in the lipid profile can be linked to the onset of age-related neurodegenerative diseases like Alzheimer's disease. Furthermore, the excessive accumulation of lipid storage organelles, lipid droplets, has significant implications for the development of inflammaging and non-communicable age-related diseases. Dietary interventions such as caloric restriction, time-restrictive eating, and lipid supplementation have been shown to improve pertinent health metrics or even extend life span and thus modulate aging processes.
    Keywords:  aging; dietary intervention; healthy life span; lipid; metabolism
  52. Front Aging. 2022 ;3 884321
      In recent years an expanding collection of heart-secreted signaling proteins have been discovered that play cellular communication roles in diverse pathophysiological processes. This minireview briefly discusses current evidence for the roles of cardiokines in systemic regulation of aging and age-associated diseases. An analysis of human transcriptome and secretome data suggests the possibility that many other cardiokines remain to be discovered that may function in long-range physiological regulations. We discuss the ongoing challenges and emerging technologies for elucidating the identity and function of cardiokines in endocrine regulations.
    Keywords:  aging; cardiokine; endocrine; heart; hiPSC; proteomics; secretome; transcriptomics
  53. Front Aging. 2022 ;3 838943
      The decreased proportion of antigen-inexperienced, naïve T cells is a hallmark of aging in both humans and mice, and contributes to reduced immune responses, particularly against novel and re-emerging pathogens. Naïve T cells depend on survival signals received during their circulation among the lymph nodes by direct contacts with stroma, in particular fibroblastic reticular cells. Macroscopic changes to the architecture of the lymph nodes have been described, but it is unclear how lymph node stroma are altered with age, and whether these changes contribute to reduced naïve T cell maintenance. Here, using 2-photon microscopy, we determined that the aged lymph node displayed increased fibrosis and correspondingly, that naïve T-cell motility was impaired in the aged lymph node, especially in proximity to fibrotic deposition. Functionally, adoptively transferred young naïve T-cells exhibited reduced homeostatic turnover in aged hosts, supporting the role of T cell-extrinsic mechanisms that regulate their survival. Further, we determined that early development of resident fibroblastic reticular cells was impaired, which may correlate to the declining levels of naïve T-cell homeostatic factors observed in aged lymph nodes. Thus, our study addresses the controversy as to whether aging impacts the composition lymph node stroma and supports a model in which impaired differentiation of lymph node fibroblasts and increased fibrosis inhibits the interactions necessary for naïve T cell homeostasis.
    Keywords:  T cell aging; fibrosis; live imaging; lymph nodes; lymphotoxin; naive T cells; two-photon microscopy
  54. Front Aging. 2021 ;2 797040
      Human immune system functions over an entire lifetime, yet how and why the immune system becomes less effective with age are not well understood. Here, we characterize peripheral blood mononuclear cell transcriptome from 132 healthy adults with 21-90 years of age using the weighted gene correlation network analyses. In our study, 113 Caucasian from the 10KIP database and RNA-seq data of 19 Asian (Chinese) are used to explore the differential co-expression genes in PBMC aging. These two dataset reveal a set of insightful gene expression modules and representative gene biomarkers for human immune system aging from Asian and Caucasian ancestry, respectively. Among them, the aging-specific modules may show an age-related gene expression variation spike around early-seventies. In addition, we find the top hub genes including NUDT7, CLPB, OXNAD1, and MLLT3 are shared between Asian and Caucasian aging related modules and further validated in human PBMCs from different age groups. Overall, the impact of age and race on transcriptional variation elucidated from this study may provide insights into the transcriptional driver of immune aging.
    Keywords:  PBMC; WGCNA; biomarkers; immune aging; race and ethnicity
  55. Front Aging. 2021 ;2 655315
      Reversible senescence at the cellular level emerged together with tissue specialization in Metazoans. However, this reversibility (ability to permanently rejuvenate) through recapitulation of early stages of development, was originally a part of ontogenesis, since the pressure of integrativeness was not dominant. The complication of specialization in phylogenesis narrowed this "freedom of maneuver", gradually "truncating" remorphogenesis to local epimorphosis and further up to the complete disappearance of remorphogenesis from the ontogenesis repertoire. This evolutionary trend transformed cellular senescence into organismal aging and any recapitulation of autonomy into carcinogenesis. The crown of specialization, Homo sapiens, completed this post-unicellular stage of development, while in the genome all the potential for the next stage of development, which can be called the stage of balanced coexistence of autonomous and integrative dominants within a single whole. Here, completing the substantiation of the new section of developmental biology, we propose to call it Developmental Biogerontology.
    Keywords:  aging; carcinogenesis; epigenetic; immunological tolerance; multicellularity; reontogenesis; senescence
  56. Neuroscience. 2022 Jul 12. pii: S0306-4522(22)00350-5. [Epub ahead of print]
      Aging is a progressive loss of physiological function that increases risk of disease and death. Among the many factors that contribute to human aging, mitochondrial dysfunction has emerged as one of the most prominent features of the aging process. It has been linked to the development of various age-related pathologies, including Parkinson's disease (PD). Mitochondria has a complex quality control system that ensures mitochondrial integrity and function. Perturbations in these mitochondrial mechanisms have long been linked to various age-related neurological disorders. Even though research has shed light on several aspects of the disease pathology, the underlying mechanism of age-related factors responsible for individuals developing this disease is still unknown. This review article aims to discuss the role of mitochondria in the transition from normal brain aging to pathological brain aging, which leads to the progression of PD. We have discussed the emerging evidence on how age-related disruption of mitochondrial quality control mechanisms contributes to the development of PD-related pathophysiology.
    Keywords:  Aging; Mitochondrial aberrations; Mitochondrial quality control mechanism; Parkinson’s disease
  57. Nat Commun. 2022 Jul 11. 13(1): 4020
      Male reproductive system ageing is closely associated with deficiency in testosterone production due to loss of functional Leydig cells, which are differentiated from stem Leydig cells (SLCs). However, the relationship between SLC differentiation and ageing remains unknown. In addition, active lipid metabolism during SLC differentiation in the reproductive system requires transportation and processing of substrates among multiple organelles, e.g., mitochondria and endoplasmic reticulum (ER), highlighting the importance of interorganelle contact. Here, we show that SLC differentiation potential declines with disordered intracellular homeostasis during SLC senescence. Mechanistically, loss of the intermediate filament Nestin results in lower differentiation capacity by separating mitochondria-ER contacts (MERCs) during SLC senescence. Furthermore, pharmacological intervention by melatonin restores Nestin-dependent MERCs, reverses SLC differentiation capacity and alleviates male reproductive system ageing. These findings not only explain SLC senescence from a cytoskeleton-dependent MERCs regulation mechanism, but also suggest a promising therapy targeting SLC differentiation for age-related reproductive system diseases.
  58. Front Aging. 2022 ;3 888190
      Ageing is a progressive physiological process mediated by changes in biological pathways, resulting in a decline in tissue and cellular function. It is a driving factor in numerous age-related diseases including cardiovascular diseases (CVDs). Cardiomyopathies, hypertension, ischaemic heart disease, and heart failure are some of the age-related CVDs that are the leading causes of death worldwide. Although individual CVDs have distinct clinical and pathophysiological manifestations, a disturbance in cellular homeostasis underlies the majority of diseases which is further compounded with aging. Three key evolutionary conserved signalling pathways, namely, autophagy, mitophagy and the unfolded protein response (UPR) are involved in eliminating damaged and dysfunctional organelle, misfolded proteins, lipids and nucleic acids, together these molecular processes protect and preserve cellular homeostasis. However, amongst the numerous molecular changes during ageing, a decline in the signalling of these key molecular processes occurs. This decline also increases the susceptibility of damage following a stressful insult, promoting the development and pathogenesis of CVDs. In this review, we discuss the role of autophagy, mitophagy and UPR signalling with respect to ageing and cardiac disease. We also highlight potential therapeutic strategies aimed at restoring/rebalancing autophagy and UPR signalling to maintain cellular homeostasis, thus mitigating the pathological effects of ageing and CVDs. Finally, we highlight some limitations that are likely hindering scientific drug research in this field.
    Keywords:  ageing; autophagy; cardiovascular disease; endoplasmic reticulum stress; mitophagy
  59. Front Aging. 2021 ;2 715981
      Our previous work has shown that young and elderly patients with Type-2 Diabetes Mellitus (T2DM) treated with Metformin have optimal B cell function and serum antibodies specific for the seasonal influenza vaccine. In this paper, we have evaluated B cell function and the metabolic requirements of B cell antibody responses in elderly T2DM patients (ET2DM) taking or not Metformin, and compared to those of healthy elderly (EH) and healthy young (YH) individuals. Results show that Metformin significantly increases in vivo B cell function, measured by influenza vaccine-specific serum antibodies, in ET2DM patients to the levels observed in EH and more importantly in YH individuals. Metformin also decreases the frequencies of pro-inflammatory B cell subsets, as well as intrinsic inflammation and metabolic requirements of peripheral B cells from ET2DM. This hyper-metabolic phenotype of B cells from ET2DM is needed to support intrinsic inflammation, measured by the expression of transcripts for markers of the senescence-associated secretory phenotype (SASP), and the secretion of autoimmune antibodies. Importantly, B cell function in ET2DM patients taking Metformin is not only increased as compared to that in ET2DM patients not taking Metformin, but is comparable to B cell function measured in YH individuals. These results altogether strongly support the anti-aging effects of Metformin on humoral immunity.
    Keywords:  B cells; Type-2 Diabetes Mellitus; aging; autoimmunity; inflammation
  60. Front Aging. 2021 ;2 719342
      Age is a major risk factor for COVID-19 severity, and T cells play a central role in anti-SARS-CoV-2 immunity. Because SARS-CoV-2-cross-reactive T cells have been detected in unexposed individuals, we investigated the age-related differences in pre-existing SARS-CoV-2-reactive T cells. SARS-CoV-2-reactive CD4+ T cells from young and elderly individuals were mainly detected in the central memory fraction and exhibited similar functionalities and numbers. Naïve-phenotype SARS-CoV-2-reactive CD8+ T cell populations decreased markedly in the elderly, while those with terminally differentiated and senescent phenotypes increased. Furthermore, senescent SARS-CoV-2-reactive CD8+ T cell populations were higher in cytomegalovirus seropositive young individuals compared to seronegative ones. Our findings suggest that age-related differences in pre-existing SARS-CoV-2-reactive CD8+ T cells may explain the poor outcomes in elderly patients and that cytomegalovirus infection is a potential factor affecting CD8+ T cell immunity against SARS-CoV-2. Thus, this study provides insights for developing effective therapeutic and vaccination strategies for the elderly.
    Keywords:  COVID-19; SARS-CoV-2; T cell aging; T-cell immunity; cross-reactive T cells; cytomegalovirus; senescent T cells
  61. Aging Cell. 2022 Jul 11. e13668
      A variety of intrinsic and extrinsic factors contribute to the altered efficiency of CTLs in elderly organisms. In particular, the efficacy of antiviral CD8+ T cells responses in the elderly has come back into focus since the COVID-19 pandemic outbreak. However, the exact molecular mechanisms leading to alterations in T cell function and the origin of the observed impairments have not been fully explored. Therefore, we investigated whether intrinsic changes affect the cytotoxic ability of CD8+ T cells in aging. We focused on the different subpopulations and time-resolved quantification of cytotoxicity during tumor cell elimination. We report a surprising result: Killing kinetics of CD8+ T cells from elderly mice are much faster than those of CD8+ T cells from adult mice. This is true not only in the total CD8+ T cell population but also for their effector (TEM ) and central memory (TCM ) T cell subpopulations. TIRF experiments reveal that CD8+ T cells from elderly mice possess comparable numbers of fusion events per cell, but significantly increased numbers of cells with granule fusion. Analysis of the cytotoxic granule (CG) content shows significantly increased perforin and granzyme levels and turns CD8+ T cells of elderly mice into very efficient killers. This highlights the importance of distinguishing between cell-intrinsic alterations and microenvironmental changes in elderly individuals. Our results also stress the importance of analyzing the dynamics of CTL cytotoxicity against cancer cells because, with a simple endpoint lysis analysis, cytotoxic differences could have easily been overlooked.
    Keywords:  CD8+ T cells; CTL; aging; cytotoxicity; granzyme; immunosenescence; perforin; tumor immunology
  62. Front Aging. 2022 ;3 903049
      Public attention and interest for longevity interventions are growing. These can include dietary interventions such as intermittent fasting, physical interventions such as various exercise regimens, or through supplementation of nutraceuticals or administration of pharmaceutics. However, it is unlikely that most interventions identified in model organisms will translate to humans, or that every intervention will benefit each person equally. In the worst case, even detrimental health effects may occur. Therefore, identifying longevity interventions using human data and tracking the aging process in people is of paramount importance as we look towards longevity interventions for the public. In this work, we illustrate how to identify candidate longevity interventions using population data in humans, an approach we have recently employed. We consider metformin as a case-study for potential confounders that influence effectiveness of a longevity intervention, such as lifestyle, sex, genetics, age of administration and the microbiome. Indeed, metformin, like most other longevity interventions, may end up only benefitting a subgroup of individuals. Fortunately, technologies have emerged for tracking the rate of 'biological' aging in individuals, which greatly aids in assessing effectiveness. Recently, we have demonstrated that even wearable devices, accessible to everyone, can be used for this purpose. We therefore propose how to use such approaches to test interventions in the general population. In summary, we advocate that 1) not all interventions will be beneficial for each individual and therefore 2) it is imperative that individuals track their own aging rates to assess healthy aging interventions.
    Keywords:  aging; biological age; chronological age; geroprotectors; interventions; public
  63. Front Aging. 2022 ;3 841796
      Aging is characterized by increased mortality, functional decline, and exponential increases in the incidence of diseases such as cancer, stroke, cardiovascular disease, neurological disease, respiratory disease, etc. Though the role of aging in these diseases is widely accepted and considered to be a common denominator, the underlying mechanisms are largely unknown. A significant age-related feature observed in many population cohorts is somatic mosaicism, the detectable accumulation of somatic mutations in multiple cell types and tissues, particularly those with high rates of cell turnover (e.g., skin, liver, and hematopoietic cells). Somatic mosaicism can lead to the development of cellular clones that expand with age in otherwise normal tissues. In the hematopoietic system, this phenomenon has generally been referred to as "clonal hematopoiesis of indeterminate potential" (CHIP) when it applies to a subset of clones in which mutations in driver genes of hematologic malignancies are found. Other mechanisms of clonal hematopoiesis, including large chromosomal alterations, can also give rise to clonal expansion in the absence of conventional CHIP driver gene mutations. Both types of clonal hematopoiesis (CH) have been observed in studies of animal models and humans in association with altered immune responses, increased mortality, and disease risk. Studies in murine models have found that some of these clonal events are involved in abnormal inflammatory and metabolic changes, altered DNA damage repair and epigenetic changes. Studies in long-lived individuals also show the accumulation of somatic mutations, yet at this advanced age, carriership of somatic mutations is no longer associated with an increased risk of mortality. While it remains to be elucidated what factors modify this genotype-phenotype association, i.e., compensatory germline genetics, cellular context of the mutations, protective effects to diseases at exceptional age, it points out that the exceptionally long-lived are key to understand the phenotypic consequences of CHIP mutations. Assessment of the clinical significance of somatic mutations occurring in blood cell types for age-related outcomes in human populations of varied life and health span, environmental exposures, and germline genetic risk factors will be valuable in the development of personalized strategies tailored to specific somatic mutations for healthy aging.
    Keywords:  CHIP; aging; clonal hematopoiesis; longevity; somatic mutations
  64. Front Aging. 2022 ;3 818700
      Respiratory infections are one of the top causes of death in the elderly population, displaying susceptibility factors with increasing age that are potentially amenable to interventions. We posit that with increasing age there are predictable tissue-specific changes that prevent the immune system from working effectively in the lung. This mini-review highlights recent evidence for altered local tissue environment factors as we age focusing on increased tissue oxidative stress with associated immune cell changes, likely driven by the byproducts of age-associated inflammatory disease. Potential intervention points are presented.
    Keywords:  aging; lung environment; oxidative stress; respiratory infections; tuberculosis
  65. Autophagy. 2022 Jul 12. 1-2
      Impaired autophagosome formation and reduced flux through the macroautophagy/autophagy pathway occurs outside the brain as part of normal aging in various species. We recently identified autophagic decline in mouse brain tissue dependent on aging. This sits alongside significantly increased expression of the Sorbs3/SORBS3/vinexin (sorbin and SH3 domain containing 3) gene in older mouse and human brains. We found that SORBS3 negatively regulates autophagy in several cell lines, including mouse primary neurons. SORBS3 depletion increases F-actin structures, which compete with YAP1-WWTR1/TAZ to bind AMOT (angiomotin) proteins in the cytosol. Unbound YAP1-WWTR1/TAZ is free to move into the nucleus and upregulate YAP1-WWTR1/TAZ target gene expression. This upregulates autophagosome formation, in part through increased expression of myosin- and actin-related genes. Moreover, we have shown these YAP1-WWTR1/TAZ target genes are downregulated in older mouse and human brains. Taken together, our findings suggest that increased SORBS3 expression contributes to autophagic decline in normal brain aging across species.
    Keywords:  Autophagy; SORBS3; YAP1-WWTR1/TAZ; brain aging; vinexin
  66. Front Aging. 2022 ;3 864860
      Lymphatic structure and function play a critical role in fluid transport, antigen delivery, and immune homeostasis. A dysfunctional lymphatic system is associated with chronic low-grade inflammation of peripheral tissues, poor immune responses, and recurrent infections, which are also hallmarks of aging pathology. Previous studies have shown that aging impairs lymphatic structure and function in a variety of organ systems, including the intestines and central nervous system. However, previous studies are mostly limited to qualitative analysis of lymphatic structural changes and quantification of intestinal collecting vessel contractile function. It is not clear whether decreased lymphatic function contributes to pathological conditions related to aging, nor how it affects the skin immune microenvironment. Further, the effects of aging on skin initial and collecting lymphatic vessels, dendritic cell (DC) migration, cutaneous lymphatic pumping, and VEGFR-3 signaling in lymphatic endothelial cells (LECs) have not been quantitatively analyzed. Here, using fluorescent immunohistochemistry and flow cytometry, we confirm that aging decreases skin initial and collecting lymphatic vessel density. Indocyanine green (ICG) lymphangiography and DC migration assays confirm that aging decreases both fluid pumping and cell migration via lymphatic vessels. At the cellular level, aging causes decreased VEGFR-3 signaling, leading to increased LEC apoptosis and senescence. Finally, we determined that aging causes decreased lymphatic production of chemokines and alters LEC expression of junctional and adhesion molecules. This in turn leads to increased peri-lymphatic inflammation and nitrosative stress that might contribute to aging pathology in a feed-forward manner. Taken together, our study, in addition to quantitatively corroborating previous findings, suggests diverse mechanisms that contribute to lymphatic dysfunction in aging that in turn exacerbate the pathology of aging in a feed-forward manner.
    Keywords:  age-related lymphatic dysfunction; decreased LEC VEGFR-3 signaling; dermal lymphatics; lymphatic endothelial apoptosis; peri-lymphatic inflammation
  67. Adv Sci (Weinh). 2022 Jul 13. e2201409
      The quest for rejuvenation and prolonged lifespan through transfusion of young blood has been studied for decades with the hope of unlocking the mystery of the key substance(s) that exists in the circulating blood of juvenile organisms. However, a pivotal mediator has yet been identified. Here, atypical findings are presented that are observed in a knockin mouse model carrying a lysine to arginine substitution at residue 74 of Krüppel-like factor 1 (KLF1/EKLF), the SUMOylation-deficient Klf1K74R/K74R mouse, that displayed significant improvement in geriatric disorders and lifespan extension. Klf1K74R/K74R mice exhibit a marked delay in age-related physical performance decline and disease progression as evidenced by physiological and pathological examinations. Furthermore, the KLF1(K74R) knockin affects a subset of lymphoid lineage cells; the abundance of tumor infiltrating effector CD8+ T cells and NKT cells is increased resulting in antitumor immune enhancement in response to tumor cell administration. Significantly, infusion of hematopoietic stem cells (HSCs) from Klf1K74R/K74R mice extends the lifespan of the wild-type mice. The Klf1K74R/K74R mice appear to be an ideal animal model system for further understanding of the molecular/cellular basis of aging and development of new strategies for antiaging and prevention/treatment of age-related diseases thus extending the healthspan as well as lifespan.
    Keywords:  KLF1/EKLF; SUMOylation; aging; antiaging; hematopoietic stem cells (HSCs)
  68. Front Aging. 2021 ;2 707372
      The mechanistic Target of Rapamycin (mTOR) is a growth-related kinase that, in the context of the mTOR complex 1 (mTORC1), touches upon most fundamental cellular processes. Consequently, its activity is a critical determinant for cellular and organismal physiology, while its dysregulation is commonly linked to human aging and age-related disease. Presumably the most important stimulus that regulates mTORC1 activity is nutrient sufficiency, whereby amino acids play a predominant role. In fact, mTORC1 functions as a molecular sensor for amino acids, linking the cellular demand to the nutritional supply. Notably, dietary restriction (DR), a nutritional regimen that has been shown to extend lifespan and improve healthspan in a broad spectrum of organisms, works via limiting nutrient uptake and changes in mTORC1 activity. Furthermore, pharmacological inhibition of mTORC1, using rapamycin or its analogs (rapalogs), can mimic the pro-longevity effects of DR. Conversely, nutritional amino acid overload has been tightly linked to aging and diseases, such as cancer, type 2 diabetes and obesity. Similar effects can also be recapitulated by mutations in upstream mTORC1 regulators, thus establishing a tight connection between mTORC1 signaling and aging. Although the role of growth factor signaling upstream of mTORC1 in aging has been investigated extensively, the involvement of signaling components participating in the nutrient sensing branch is less well understood. In this review, we provide a comprehensive overview of the molecular and cellular mechanisms that signal nutrient availability to mTORC1, and summarize the role that nutrients, nutrient sensors, and other components of the nutrient sensing machinery play in cellular and organismal aging.
    Keywords:  aging; amino acids; dietary restriction; mTORC1; nutrient sensing
  69. Life Sci Alliance. 2022 Nov;pii: e202201531. [Epub ahead of print]5(11):
      Mitochondria-ER contact sites (MERCs) orchestrate many important cellular functions including regulating mitochondrial quality control through mitophagy and mediating mitochondrial calcium uptake. Here, we identify and functionally characterize the Drosophila ortholog of the recently identified mammalian MERC protein, Pdzd8. We find that reducing pdzd8-mediated MERCs in neurons slows age-associated decline in locomotor activity and increases lifespan in Drosophila. The protective effects of pdzd8 knockdown in neurons correlate with an increase in mitophagy, suggesting that increased mitochondrial turnover may support healthy aging of neurons. In contrast, increasing MERCs by expressing a constitutive, synthetic ER-mitochondria tether disrupts mitochondrial transport and synapse formation, accelerates age-related decline in locomotion, and reduces lifespan. Although depletion of pdzd8 prolongs the survival of flies fed with mitochondrial toxins, it is also sufficient to rescue locomotor defects of a fly model of Alzheimer's disease expressing Amyloid β42 (Aβ42). Together, our results provide the first in vivo evidence that MERCs mediated by the tethering protein pdzd8 play a critical role in the regulation of mitochondrial quality control and neuronal homeostasis.
  70. J Genet Genomics. 2022 Jul 12. pii: S1673-8527(22)00182-5. [Epub ahead of print]
      Reproductive aging is a natural process conserved across species and is well-known in females. It shows age-related follicle depletion and reduction of oocyte quality, eventually causing reproductive senescence and menopause. Although reproductive aging in males is not well noticed as in females, it also causes infertility and has deleterious consequences on the offspring. Many factors have been suggested to contribute to reproductive aging, including oxidative stress, mitochondrial defects, telomere shortening, meiotic chromosome segregation errors, genetic alterations, etc. With the increasing trend of pregnancy age, it is particularly crucial to find interventions to preserve or extend human fertility. Studies in humans and model organisms have provided insights into the biological pathways associated with reproductive aging, and a series of potential interventive strategies have been tested. Here, we review factors affecting reproductive aging in females and males and summarize interventive strategies that may help delay or rescue the aging phenotypes of reproduction.
    Keywords:  gamete quality; infertility; oocytes; reproductive aging; sperm
  71. Immunity. 2022 Jul 07. pii: S1074-7613(22)00280-1. [Epub ahead of print]
      Mitochondrial DNA (mtDNA) escaping stressed mitochondria provokes inflammation via cGAS-STING pathway activation and, when oxidized (Ox-mtDNA), it binds cytosolic NLRP3, thereby triggering inflammasome activation. However, it is unknown how and in which form Ox-mtDNA exits stressed mitochondria in non-apoptotic macrophages. We found that diverse NLRP3 inflammasome activators rapidly stimulated uniporter-mediated calcium uptake to open mitochondrial permeability transition pores (mPTP) and trigger VDAC oligomerization. This occurred independently of mtDNA or reactive oxygen species, which induce Ox-mtDNA generation. Within mitochondria, Ox-mtDNA was either repaired by DNA glycosylase OGG1 or cleaved by the endonuclease FEN1 to 500-650 bp fragments that exited mitochondria via mPTP- and VDAC-dependent channels to initiate cytosolic NLRP3 inflammasome activation. Ox-mtDNA fragments also activated cGAS-STING signaling and gave rise to pro-inflammatory extracellular DNA. Understanding this process will advance the development of potential treatments for chronic inflammatory diseases, exemplified by FEN1 inhibitors that suppressed interleukin-1β (IL-1β) production and mtDNA release in mice.
    Keywords:  FEN1; NLRP3 inflammasome; OGG1; Ox-mtDNA; VDAC; cGAS-STING; mPTP; mitochondria; mtDNA
  72. Front Aging. 2021 ;2 746295
      Respiratory infection caused by Streptococcus pneumoniae is a leading cause of morbidity and mortality in older adults. Acquired CD4+ T cell mechanism are essential for the protection against colonization and subsequent development of infections by S. pneumoniae. In this study, we hypothesized that age-related changes within the CD4+ T-cell population compromise CD4+ T-cell specific responses to S. pneumoniae, thereby contributing to increased susceptibility at older age. To this end, we interrogated the CD4+ T-cell response against the immunogenic pneumococcal protein AliB, part of the unique oligopeptide ABC transporter system responsible for the uptake of nutrients for the bacterium and crucial for the development of pneumococcal meningitis, in healthy young and older adults. Specifically, proliferation of CD4+ T cells as well as concomitant cytokine profiles and phenotypic markers implied in immunosenescence were studied. Older adults showed decreased AliB-induced CD4+ T-cell proliferation that is associated with an increased frequency of regulatory T cells and lower levels of active CD25+CD127+CTLA-4-TIGIT-CD4+T cells. Additionally, levels of pro-inflammatory cytokines IFNy and IL-17F were decreased at older age. Our findings indicate that key features of a pneumococcal-specific CD4+ T-cell immune response are altered at older age, which may contribute to enhanced susceptibility for pneumococcal infections.
    Keywords:  CD4+ T cells; Streptococcus pneumoniae; aging; immunosenescence; infection; pneumococcal proteins; proinflammatory cytokines; tregs
  73. Cell Metab. 2022 Jul 08. pii: S1550-4131(22)00230-3. [Epub ahead of print]
      Hepatocellular carcinoma (HCC) is a typically fatal malignancy exhibiting genetic heterogeneity and limited therapy responses. We demonstrate here that HCCs consistently repress urea cycle gene expression and thereby become auxotrophic for exogenous arginine. Surprisingly, arginine import is uniquely dependent on the cationic amino acid transporter SLC7A1, whose inhibition slows HCC cell growth in vitro and in vivo. Moreover, arginine deprivation engages an integrated stress response that promotes HCC cell-cycle arrest and quiescence, dependent on the general control nonderepressible 2 (GCN2) kinase. Inhibiting GCN2 in arginine-deprived HCC cells promotes a senescent phenotype instead, rendering these cells vulnerable to senolytic compounds. Preclinical models confirm that combined dietary arginine deprivation, GCN2 inhibition, and senotherapy promote HCC cell apoptosis and tumor regression. These data suggest novel strategies to treat human liver cancers through targeting SLC7A1 and/or a combination of arginine restriction, inhibition of GCN2, and senolytic agents.
    Keywords:  GCN2; arginine; hepatocellular carcinoma; senescence; urea cycle
  74. Front Aging. 2022 ;3 909509
      Intestinal microbial communities participate in essential aspects of host biology, including nutrient acquisition, development, immunity, and metabolism. During host aging, dramatic shifts occur in the composition, abundance, and function of the gut microbiota. Although such changes in the microbiota are conserved across species, most studies remain descriptive and at most suggest a correlation between age-related pathology and particular microbes. Therefore, the causal role of the microbiota in host aging has remained a challenging question, in part due to the complexity of the mammalian intestinal microbiota, most of which is not cultivable or genetically amenable. Here, we summarize recent studies in the fruit fly Drosophila melanogaster that have substantially progressed our understanding at the mechanistic level of how gut microbes can modulate host aging.
    Keywords:  aging; drosophila; dysbiosis; dysplasia; intestinal immunity; lifespan; microbiota
  75. Front Aging. 2021 ;2 678543
      Growing life expectancy will contribute to the on-going shift towards a world population increasingly comprised of elderly individuals. This demographic shift is associated with a rising prevalence of age-related diseases, among all age-related pathologies it has become crucial to understand the age-associated cognitive changes that remain a major risk factor for the development of vascular cognitive impairment and dementia (VCID). Furthermore, age-related Alzheimer's disease and other neurogenerative diseases with vascular etiology are the most prominent contributing factors for the loss of cognitive function observed in aging. Hyperbaric Oxygen Therapy (HBOT) achieves physiologic effects by increasing oxygen tension (PO2), raising oxygen tissue levels, decreasing intracranial pressure and relieving cerebral edema. Many of the beneficial effects of HBOT exert their protective effects at the level of the microcirculation. Furthermore, the microcirculation's exquisite pervasive presence across every tissue in the body, renders it uniquely able to influence the local environment of most tissues and organs, including the brain. As such, treatments aimed at restoring aging-induced functional and structural alterations of the cerebral microcirculation may potentially contribute to the amelioration of a range of age-related pathologies including vascular cognitive impairment, Alzheimer's disease, and vascular dementias. Despite the presented evidence, the efficacy and safety of HBOT for the treatment of age-related vascular cognitive impairment and dementia remains understudied. The present review aims to examine the existing evidence indicative of a potential therapeutic role for HBOT-induced hyperoxia against age-related cerebromicrovascular pathologies contributing to cognitive impairment, dementia and decreased healthspan in the elderly.
    Keywords:  aging; aging, dementia; cognitive function; geroscience; neurodegeneration; neurovascular coupling
  76. Biomed J. 2022 Jul 07. pii: S2319-4170(22)00101-9. [Epub ahead of print]
      BACKGROUND: The aging-induced decrease in intestinal barrier function contributes to many age-related diseases. Studies on preventive measures for "leaky gut" may help improve the quality of life of geriatric patients. The potent anti-aging effect of Gastrodia elata and parishin, which is one of its active ingredients, has been reported previously. However, their effects on the gut remain elusive, and the effect of parishin on mammals has not been studied.MATERIAL AND METHODS: We used quantitative RT-PCR, western blotting, immunohistochemical analysis, and 16S rRNA sequencing to investigate the effect of Gastrodia elata and parishin on the intestinal barrier function of D-Gal-induced aging mice.
    RESULTS: Gastrodia elata and parishin prevented the decrease in tight junction protein expression and morphological changes, modulated the composition of fecal microbiota to a healthier state, and reversed the translocation of microbial toxins and systemic inflammation. The correlation analyses showed that tight junction protein expression and systemic inflammation were significantly positively or negatively correlated with the composition of fecal microbiota after Gastrodia elata and parishin administration. Additionally, tight junction protein expression was also correlated with systemic inflammation. Moreover, Gastrodia elata and parishin administration reversed the decreased or increased expression of aging-related biomarkers, such as FOXO3a, SIRT1, CASPASE3 and P21, in the gut.
    CONCLUSIONS: These results suggested that G. elata and parishin could prevent gut aging and ameliorate the "leaky gut" of aged mice and that the underlying mechanism is related to the mutual correlations among barrier function, fecal microbiota composition, and inflammation.
    Keywords:  Gastrodia elata; aging; fecal microbiota; inflammation; intestinal barrier function; parishin
  77. Curr Med Chem. 2022 Jul 13.
      INTRODUCTION: Aging is characterized as a syndrome of deleterious, progressive, universal, and irreversible function changes affecting every structural and functional aspect of the organism and accompanied by a generalized increase in mortality. Although a substantial number of candidates for biomarkers of aging have been proposed, none has been validated or universally accepted. Human telomeres constitute hexameric repetitive DNA sequence nucleoprotein complexes that cap chromosome ends, regulating gene expression and modulating stress-related pathways. Telomere length (TL) shortening is observed both in cellular senescence and advanced age, leading to the investigation of TL as a biomarker for aging and a risk factor indicator for the development and progression of the most common age-related diseases.OBJECTIVE: The present review underlines the connection between TL and the pathophysiology of the diseases associated with telomere attrition.
    METHODS: We performed a structured search of the PubMed database for peer-reviewed research of the literature regarding leukocyte TL and cardiovascular diseases (CVD), more specifically stroke and heart disease, and focused on the relevant articles published during the last 5 years. We also applied Hill's criteria of causation to strengthen this association.
    RESULTS: We analyzed the recent literature regarding TL length, stroke, and CVD. Although approximately one-third of the available studies support the connection, the results of different studies seem to be rather conflicting as a result of different study designs, divergent methods of TL determination, small study samples, and patient population heterogeneity. After applying Hill's criteria, we can observe that the literature conforms to them weakly, with chronology being the only Hill criterion of causality that probably cannot be contested.
    CONCLUSION: The present review attempted to examine the purported relation between leukocyte TL and age-related diseases such as CVD and more specific stroke and heart disease in view of the best established, comprehensive, medical and epidemiological criteria that have characterized the focused recent relevant research. Although several recommendations have been made that may contribute significantly to the field, a call for novel technical approaches and studies is mandatory to further elucidate the possible association.
    Keywords:  Cardiovascular Disease; Heart Disease; Hill’s Criteria; Stroke; Telomere Length
  78. Aging (Albany NY). 2022 Jul 12. 14(undefined):
      In the U.S. about half of the HIV-infected individuals are aged 50 and older. In men living with HIV, secondary hypogonadism is common and occurs earlier than in seronegative men, and its prevalence increases with age. While the mechanisms(s) are unknown, the HIV-1 trans-activator of transcription (Tat) protein disrupts neuroendocrine function in mice partly by dysregulating mitochondria and neurosteroidogenesis. We hypothesized that conditional Tat expression in middle-aged male transgenic mice [Tat(+)] would promote age-related comorbidities compared to age-matched controls [Tat(-)]. We expected Tat to alter steroid hormone milieu consistent with behavioral deficits. Middle-aged Tat(+) mice had lower circulating testosterone and progesterone than age-matched controls and greater circulating corticosterone and central allopregnanolone than other groups. Young Tat(+) mice had greater circulating progesterone and estradiol-to-testosterone ratios. Older age or Tat exposure increased anxiety-like behavior (open field; elevated plus-maze), increased cognitive errors (radial arm water maze), and reduced grip strength. Young Tat(+), or middle-aged Tat(-), males had higher mechanical nociceptive thresholds than age-matched counterparts. Steroid levels correlated with behaviors. Thus, Tat may contribute to HIV-accelerated aging.
    Keywords:  aging; hypothalamic-pituitary-adrenal axis; hypothalamic-pituitary-gonadal axis; secondary hypogonadism; trans-activating transcriptor
  79. Front Aging. 2022 ;3 916118
      Since its introduction as a genetic model organism, Caenorhabditis elegans has yielded insights into the causes of aging. In addition, it has provided a molecular understanding of mechanisms of neurodegeneration, one of the devastating effects of aging. However, C. elegans has been less popular as an animal model to investigate DNA repair and genomic instability, which is a major hallmark of aging and also a cause of many rare neurological disorders. This article provides an overview of DNA repair pathways in C. elegans and the impact of DNA repair on aging hallmarks, such as mitochondrial dysfunction, telomere maintenance, and autophagy. In addition, we discuss how the combination of biological characteristics, new technical tools, and the potential of following precise phenotypic assays through a natural life-course make C. elegans an ideal model organism to study how DNA repair impact neurodegeneration in models of common age-related neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Caenorhabditis elegans; DNA repair; Parkinson’s disease; aging; neurodegenerative diseases
  80. Front Aging. 2021 ;2 709914
      Human life span expectancy has increased, and aging affects the organism in several ways, leading, for example, to an increased risk of cardiovascular diseases. Age-adjusted prevalence of the cardiovascular diseases is higher in males than females. Aging also affects the gonadal sex hormones and the sex differences observed in cardiovascular diseases may be therefore impacted. Hormonal changes associated with aging may also affect the immune system and the immune response is sexually different. The immune system plays a role in the pathogenesis of cardiovascular diseases. In this context, toll-like receptors (TLRs) are a family of pattern recognition receptors of the immune system whose activation induces the synthesis of pro-inflammatory molecules. They are expressed throughout the cardiovascular system and their activation has been widely described in cardiovascular diseases. Some recent evidence demonstrates that there are sex differences associated with TLR responses and that these receptors may be affected by sex hormones and their receptors, suggesting that TLRs may contribute to the sex differences observed in cardiovascular diseases. Recent evidence also shows that sex differences of TLRs in cardiovascular system persists with aging, which may represent a new paradigm about the mechanisms that contribute to the sex differences in cardiovascular aging. Therefore, in this mini review we describe the latest findings regarding the sex differences of TLRs and associated signaling in cardiovascular diseases during aging.
    Keywords:  cardiovascular aging; cardiovascular disease; sex difference; sex hormone; toll-like receptor