bims-senagi Biomed News
on Senescence and aging
Issue of 2022‒03‒27
thirty-one papers selected by
Maria Grazia Vizioli
Mayo Clinic

  1. Front Bioeng Biotechnol. 2022 ;10 823945
      Intervertebral disc degeneration (IVDD) is the main cause of cervical and lumbar spondylosis. Over the past few years, the relevance between cellular senescence and IVDD has been widely studied, and the senescence-associated secretory phenotype (SASP) produced by senescent cells is found to remodel extracellular matrix (ECM) metabolism and destruct homeostasis. Elimination of senescent cells by senolytics and suppression of SASP production by senomorphics/senostatics are effective strategies to alleviate degenerative diseases including IVDD. Here, we review the involvement of senescence in the process of IVDD; we also discuss the potential of senolytics on eliminating senescent disc cells and alleviating IVDD; finally, we provide a table listing senolytic drugs and small molecules, aiming to propose potential drugs for IVDD therapy in the future.
    Keywords:  IVDD; SASP; aging; cellular senescence; intervertebral disc degeneration; senescence-associated secretory phenotype; senolytic
  2. Cells. 2022 Mar 17. pii: 1017. [Epub ahead of print]11(6):
      Aging is the greatest risk factor for nearly all major chronic diseases, including cardiovascular diseases, cancer, Alzheimer's and other neurodegenerative diseases of aging. Age-related impairment of immune function (immunosenescence) is one important cause of age-related morbidity and mortality, which may extend beyond its role in infectious disease. One aspect of immunosenescence that has received less attention is age-related natural killer (NK) cell dysfunction, characterized by reduced cytokine secretion and decreased target cell cytotoxicity, accompanied by and despite an increase in NK cell numbers with age. Moreover, recent studies have revealed that NK cells are the central actors in the immunosurveillance of senescent cells, whose age-related accumulation is itself a probable contributor to the chronic sterile low-grade inflammation developed with aging ("inflammaging"). NK cell dysfunction is therefore implicated in the increasing burden of infection, malignancy, inflammatory disorders, and senescent cells with age. This review will focus on recent advances and open questions in understanding the interplay between systemic inflammation, senescence burden, and NK cell dysfunction in the context of aging. Understanding the factors driving and enforcing NK cell aging may potentially lead to therapies countering age-related diseases and underlying drivers of the biological aging process itself.
    Keywords:  aging; cytokines; elderly; frailty; immune system; immunosenescence; inflammation; natural killer cells (NK cells); senescence
  3. Aging Cell. 2022 Mar 21. e13594
      Disproportionately high incidence and mortality of respiratory infection such as influenza A virus (IAV) and SARS-CoV-2 have been evidenced in the elderly, but the role and the mechanism of age-associated immune deregulation in disease exacerbation are not well defined. Using a late generation of mice deficient in telomerase RNA (Terc-/- ), we herein demonstrated that aged mice were exquisitely susceptible to respiratory viral infection, with excessive inflammation and increased mortality. Furthermore, we identified the cGAS/STING pathway, which was essentially induced by the leaked mitochondrial DNA, as a biologically relevant mechanism contributing to exaggerated inflammation in Terc-/- mice following viral infection. Innate immune cells, mainly, macrophages with shortened telomeres, exhibited hallmarks of cellular senescence, mitochondrial distress, and aberrant activation of STING and NLRP3 inflammasome pathways, which predisposed mice to severe viral pneumonia during commonly mild infections. Application of STING inhibitor and, more importantly, senolytic agent, reduced the burden of stressed macrophages, improved mitochondrial integrity, and suppressed STING activation, thereby conferring the protection for Terc-/- mice against respiratory infection. Together, the findings expand our understanding of innate immune senescence and reveal the potential of the senolytics as a promising treatment to alleviate the symptom of viral pneumonia, particularly for the older population.
    Keywords:  STING; macrophage; respiratory virus infection; senescence; telomere
  4. Geroscience. 2022 Mar 24.
      With aging, skeletal muscle plasticity is attenuated in response to exercise. Here, we report that senescent cells, identified using senescence-associated β-galactosidase (SA β-Gal) activity and p21 immunohistochemistry, are very infrequent in resting muscle, but emerge approximately 2 weeks after a bout of resistance exercise in humans. We hypothesized that these cells contribute to blunted hypertrophic potential in old age. Using synergist ablation-induced mechanical overload (MOV) of the plantaris muscle to model resistance training in adult (5-6-month) and old (23-24-month) male C57BL/6 J mice, we found increased senescent cells in both age groups during hypertrophy. Consistent with the human data, there were negligible senescent cells in plantaris muscle from adult and old sham controls, but old mice had significantly more senescent cells 7 and 14 days following MOV relative to young. Old mice had blunted whole-muscle hypertrophy when compared to adult mice, along with smaller muscle fibers, specifically glycolytic type 2x + 2b fibers. To ablate senescent cells using a hit-and-run approach, old mice were treated with vehicle or a senolytic cocktail consisting of 5 mg/kg dasatinib and 50 mg/kg quercetin (D + Q) on days 7 and 10 during 14 days of MOV; control mice underwent sham surgery with or without senolytic treatment. Old mice given D + Q had larger muscles and muscle fibers after 14 days of MOV, fewer senescent cells when compared to vehicle-treated old mice, and changes in the expression of genes (i.e., Igf1, Ddit4, Mmp14) that are associated with hypertrophic growth. Our data collectively show that senescent cells emerge in human and mouse skeletal muscle following a hypertrophic stimulus and that D + Q improves muscle growth in old mice.
    Keywords:  Anabolic resistance; Hypertrophy; Senescence; Senolytics; Skeletal muscle
  5. Pediatr Nephrol. 2022 Mar 26.
      Acute kidney injury (AKI) is a common clinical complication characterized by a sudden deterioration of the kidney's excretory function, which normally occurs secondary to another serious illness. AKI is an important risk factor for chronic kidney disease (CKD) occurrence and progression to kidney failure. It is, therefore, crucial to block the development of AKI as early as possible. To date, existing animal studies have shown that senescence occurs in the early stage of AKI and is extremely critical to prognosis. Cellular senescence is an irreversible process of cell cycle arrest that is accompanied by alterations at the transcriptional, metabolic, and secretory levels along with modified cellular morphology and chromatin organization. Acute cellular senescence tends to play an active role, whereas chronic senescence plays a dominant role in the progression of AKI to CKD. The occurrence of chronic senescence is inseparable from senescence-associated secretory phenotype (SASP) and senescence-related pathways. SASP acts on normal cells to amplify the senescence signal through senescence-related pathways. Senescence can be improved by initiating reprogramming, which plays a crucial role in blocking the progression of AKI to CKD. This review integrates the existing studies on senescence in AKI from several aspects to find meaningful research directions to improve the prognosis of AKI and prevent the progression of CKD.
    Keywords:  Acute kidney injury; Chronic kidney disease; Senescence; Senescence-associated secretory phenotype
  6. J Tissue Eng Regen Med. 2022 Mar 23.
      Chronic ischemia triggers senescence in renal tubules and at least partly mediates kidney dysfunction and damage through a p16Ink4a -related mechanism. We previously showed that mesenchymal stromal/stem cells (MSCs) delivered systemically do not effectively decrease cellular senescence in stenotic murine kidneys. We hypothesized that selective MSC targeting to injured kidneys using an anti-KIM1 antibody (KIM-MSC) coating would enhance their ability to abrogate cellular senescence in murine renal artery stenosis (RAS). KIM-MSC were injected into transgenic INK-ATTAC mice, which are amenable for selective eradication of p16Ink4a+ cells, 4 weeks after induction of unilateral RAS. To determine whether KIM-MSC abolish p16Ink4a -dependent cellular senescence, selective clearance of p16Ink4a+ cells was induced in a subgroup of RAS mice using AP20187 over 3 weeks prior to KIM-MSC injection. Two weeks after KIM-MSC aortic injection, renal senescence, function, and tissue damage were assessed. KIM-MSC delivery decreased gene expression of senescence and senescence-associated secretory phenotype factors, and improved micro-MRI-derived stenotic-kidney glomerular filtration rate and perfusion. Renal fibrosis and tubular injury also improved after KIM-MSC treatment. Yet, their efficacy was slightly augmented by prior elimination of p16Ink4a+ senescent cells. Therefore, selective targeting of MSC to the injured kidney markedly improves their senolytic potency in murine RAS, despite incomplete eradication of p16+ cells. KIM-MSC may constitute a useful therapeutic strategy in chronic renal ischemic injury.
    Keywords:  cellular senescence; kidney injury molecule-1; mesenchymal stem cells; renal artery stenosis
  7. Front Cell Dev Biol. 2022 ;10 786031
      It is widely believed that cellular senescence plays a critical role in both aging and cancer, and that senescence is a fundamental, permanent growth arrest that somatic cells cannot avoid. Here we show that Myc plays an important role in self-renewal of esophageal epithelial cells, contributing to their resistance to cellular senescence. Myc is homogeneously expressed in basal cells of the esophageal epithelium and Myc positively regulates their self-renewal by maintaining their undifferentiated state. Indeed, Myc knockout induced a loss of the undifferentiated state of esophageal epithelial cells resulting in cellular senescence while forced MYC expression promoted oncogenic cell proliferation. A superoxide scavenger counteracted Myc knockout-induced senescence, therefore suggesting that a mitochondrial superoxide takes part in inducing senescence. Taken together, these analyses reveal extremely low levels of cellular senescence and senescence-associated phenotypes in the esophageal epithelium, as well as a critical role for Myc in self-renewal of basal cells in this organ. This provides new avenues for studying and understanding the links between stemness and resistance to cellular senescence.
    Keywords:  MYC; aging; cancer; mitochondria highlights; senescence
  8. Antioxidants (Basel). 2022 Feb 28. pii: 480. [Epub ahead of print]11(3):
      Cell senescence is critical in diverse aspects of organism life. It is involved in tissue development and homeostasis, as well as in tumor suppression. Consequently, it is tightly integrated with basic physiological processes during life. On the other hand, senescence is gradually being considered as a major contributor of organismal aging and age-related diseases. Increased oxidative stress is one of the main risk factors for cellular damages, and thus a driver of senescence. In fact, there is an intimate link between cell senescence and response to different types of cellular stress. Oxidative stress occurs when the production of reactive oxygen species/reactive nitrogen species (ROS/RNS) is not adequately detoxified by the antioxidant defense systems. Non-coding RNAs are endogenous transcripts that govern gene regulatory networks, thus impacting both physiological and pathological events. Among these molecules, microRNAs, long non-coding RNAs, and more recently circular RNAs are considered crucial mediators of almost all cellular processes, including those implicated in oxidative stress responses. Here, we will describe recent data on the link between ROS/RNS-induced senescence and the current knowledge on the role of non-coding RNAs in the senescence program.
    Keywords:  aging; cell senescence; circular RNAs; long non-coding RNAs; microRNAs; non-coding RNAs; oxidative stress; redox homeostasis
  9. Oncoimmunology. 2022 ;11(1): 2052411
      Epithelial ovarian carcinoma (EOC) is virtually insensitive to immune checkpoint inhibitors (ICIs). Recent findings from an innovative mouse model of EOC demonstrate that senescence induction underlies the increased sensitivity of homologous recombination-defective EOCs to platinum-based chemotherapy as it initiates tumor infiltration by immune effector cells coupled to restored sensitivity to ICIs.
    Keywords:  BRCA1/2; CGAS; GEMM; NK cells; PD-1; senescence-associated secretory phenotype
  10. Front Cell Dev Biol. 2022 ;10 829404
      Chemotherapy-induced senescence promotes immunocyte aggregation in the tumor microenvironment by upregulating the surface expression of activating ligands in cancer cells. However, these senescent tumor cells cannot be completely cleared and can induce tumor recurrence. Previous studiesshowed that soluble natural killer (NK) group 2D (NKG2D) ligands impair the recognition of multiple immune cells. In this study, we established an in vitro senescence model using neuroblastoma cells subjected to low-dose Chemotherapeutic drug doxorubicin or the Aurora A inhibitor MLN8237. The results showed that different neuroblastoma cell lines showed increased secretion of the NKG2D ligand MHC class I polypeptide-related sequence A/B (MICA/B) following proteolysis after treatment, with MICA/B subsequently recruited to exosomes to downregulate NKG2D expression in NK cells. Interestingly, disintegrin and metalloproteinase domain-containing 10 (ADAM10) was upregulated in senescent tumor cells, and combined treatment with the ADAM10 inhibitor GI254023X and chemotherapeutic drugs inhibited MICA/B secretion and enhanced recognition and killing by NK cells. Additionally, we found that expression of the long noncoding RNA MALAT1 was significantly increased in senescent neuroblastoma cells, and that MALAT1 served as a sponge for microRNA (miR)-92a-3p to counteract miR-92a-3p-mediated repression of ADAM10 levels. Furthermore, administration of a MALAT1 inhibitor or an miR-92a-3p mimic reduced the MICA/B shedding and enhanced recognition and killing by NK cells. These results confirmed that low-dose chemotherapy induces senescence in neuroblastoma cells, and that senescent tumor cells promote the shedding of the NKG2D ligand MICA/B through the MALAT1/miR-92a/ADAM10 axis, thereby contributing to the formation of a suppressive immune microenvironment and promoting immune escape.
    Keywords:  NKG2D; exosome; immune escape; neuroblastoma; senescence-associated secretory phenotype
  11. Aging (Albany NY). 2022 Mar 21. 14(undefined):
      Heterochronic parabiosis is used to study the systemic effects of aging and involves surgically connecting two animals of different ages such that they have common blood circulation. Although this technique has been prevalent for a long time, there is no scientific consensus on the age of the animals that should be used. We hypothesized that the younger the animal, the greater would be its rejuvenating effect. Hence, to test this hypothesis, we created parabiosis of 67-week-old mice with younger mice of different ages (4-week-old and 8-week-old). We evaluated the changes in appearance and the expression IL-1A, IL-6, and Cdkn2a (p16) in the liver, kidney, brain, and skin. These cytokines belong to the senescence-associated secretory phenotype (SASP) factors, and are indicators of aging. Although we did not find any significant changes in the appearance of the mice, we found statistically significant differences in some SASP factors between the liver of the 4-week-old and 8-week-old pairs. However, overall, compared to the 8-week-old mice, the 4-week-old does not exert a significantly higher rejuvenation effect on the older mice. Hence, we concluded that the rejuvenation of older mice during heterochronic parabiosis might not be affected by the exact age of the younger mice.
    Keywords:  aging; heterochronic parabiosis; inflammatory cytokines; rejuvenating effect; senescence-associated secretory phenotype
  12. Cancers (Basel). 2022 Mar 12. pii: 1460. [Epub ahead of print]14(6):
      Radiotherapy (RT) is a key component of cancer treatment. Although improvements have been made over the years, radioresistance remains a challenge. For this reason, a better understanding of cell fates in response to RT could improve therapeutic options to enhance cell death and reduce adverse effects. Here, we showed that combining RT (photons and protons) to noncytotoxic concentration of PARP inhibitor, Olaparib, induced a cell line-dependent senescence-like phenotype. The senescent cells were characterized by morphological changes, an increase in p21 mRNA expression as well as an increase in senescence-associated β-galactosidase activity. We demonstrated that these senescent cells could be specifically targeted by Navitoclax (ABT-263), a Bcl-2 family inhibitor. This senolytic drug led to significant cell death when combined with RT and Olaparib, while limited cytotoxicity was observed when used alone. These results demonstrate that a combination of RT with PARP inhibition and senolytics could be a promising therapeutic approach for cancer patients.
    Keywords:  PARP; X-ray radiation; cancer; proton radiation; senescence; senolytics
  13. Int J Mol Sci. 2022 Mar 11. pii: 3028. [Epub ahead of print]23(6):
      Comprehensive proteomics studies of human hematopoietic stem and progenitor cells (HSPC) have revealed that aging of the HSPC compartment is characterized by elevated glycolysis. This is in addition to deregulations found in murine transcriptomics studies, such as an increased differentiation bias towards the myeloid lineage, alterations in DNA repair, and a decrease in lymphoid development. The increase in glycolytic enzyme activity is caused by the expansion of a more glycolytic HSPC subset. We therefore developed a method to isolate HSPC into three distinct categories according to their glucose uptake (GU) levels, namely the GUhigh, GUinter and GUlow subsets. Single-cell transcriptomics studies showed that the GUhigh subset is highly enriched for HSPC with a differentiation bias towards myeloid lineages. Gene set enrichment analysis (GSEA) demonstrated that the gene sets for cell cycle arrest, senescence-associated secretory phenotype, and the anti-apoptosis and P53 pathways are significantly upregulated in the GUhigh population. With this series of studies, we have produced a comprehensive proteomics and single-cell transcriptomics atlas of molecular changes in human HSPC upon aging. Although many of the molecular deregulations are similar to those found in mice, there are significant differences. The most unique finding is the association of elevated central carbon metabolism with senescence. Due to the lack of specific markers, the isolation and collection of senescent cells have yet to be developed, especially for human HSPC. The GUhigh subset from the human HSPC compartment possesses all the transcriptome characteristics of senescence. This property may be exploited to accurately enrich, visualize, and trace senescence development in human bone marrow.
    Keywords:  aging; central carbon metabolism; glycolysis; hematopoietic stem and progenitor cells; senescence signature
  14. Int J Mol Sci. 2022 Mar 21. pii: 3374. [Epub ahead of print]23(6):
      CD8+ T lymphocytes are a heterogeneous class of cells that play a crucial role in the adaptive immune response against pathogens and cancer. During their lifetime, they acquire cytotoxic functions to ensure the clearance of infected or transformed cells and, in addition, they turn into memory lymphocytes, thus providing a long-term protection. During ageing, the thymic involution causes a reduction of circulating T cells and an enrichment of memory cells, partially explaining the lowering of the response towards novel antigens with implications in vaccine efficacy. Moreover, the persistent stimulation by several antigens throughout life favors the switching of CD8+ T cells towards a senescent phenotype contributing to a low-grade inflammation that is a major component of several ageing-related diseases. In genetically predisposed young people, an immunological stress caused by viral infections (e.g., HIV, CMV, SARS-CoV-2), autoimmune disorders or tumor microenvironment (TME) could mimic the ageing status with the consequent acceleration of T cell senescence. This, in turn, exacerbates the inflamed conditions with dramatic effects on the clinical progression of the disease. A better characterization of the phenotype as well as the functions of senescent CD8+ T cells can be pivotal to prevent age-related diseases, to improve vaccine strategies and, possibly, immunotherapies in autoimmune diseases and cancer.
    Keywords:  CD28− CD57+ CD8+ T cells; CMV; HIV; SARS-CoV-2; autoimmune disease; cancer; immune-senescence; infection; inflammaging
  15. Mol Cell Biochem. 2022 Mar 25.
      The nicotinamide adenine dinucleotide (NAD+) is an essential redox cofactor, involved in various physiological and molecular processes, including energy metabolism, epigenetics, aging, and metabolic diseases. NAD+ repletion ameliorates muscular dystrophy and improves the mitochondrial and muscle stem cell function and thereby increase lifespan in mice. Accordingly, NAD+ is considered as an anti-oxidant and anti-aging molecule. NAD+ plays a central role in energy metabolism and the energy produced is used for movements, thermoregulation, and defense against foreign bodies. The dietary precursors of NAD+ synthesis is targeted to improve NAD+ biosynthesis; however, studies have revealed conflicting results regarding skeletal muscle-specific effects. Recent advances in the activation of nicotinamide phosphoribosyltransferase in the NAD+ salvage pathway and supplementation of NAD+ precursors have led to beneficial effects in skeletal muscle pathophysiology and function during aging and associated metabolic diseases. NAD+ is also involved in the epigenetic regulation and post-translational modifications of proteins that are involved in various cellular processes to maintain tissue homeostasis. This review provides detailed insights into the roles of NAD+ along with molecular mechanisms during aging and disease conditions, such as the impacts of age-related NAD+ deficiencies on NAD+-dependent enzymes, including poly (ADP-ribose) polymerase (PARPs), CD38, and sirtuins within skeletal muscle, and the most recent studies on the potential of nutritional supplementation and distinct modes of exercise to replenish the NAD+ pool.
    Keywords:  Aging; Diabetes; Epigenetics; Muscle diseases; NAD+; Redox
  16. Sci Rep. 2022 Mar 25. 12(1): 5196
      Aging in mammals leads to reduction in genes encoding the 45-subunit mitochondrial electron transport chain complex I. It has been hypothesized that normal aging and age-related diseases such as Parkinson's disease are in part due to modest decrease in expression of mitochondrial complex I subunits. By contrast, diminishing expression of mitochondrial complex I genes in lower organisms increases lifespan. Furthermore, metformin, a putative complex I inhibitor, increases healthspan in mice and humans. In the present study, we investigated whether loss of one allele of Ndufs2, the catalytic subunit of mitochondrial complex I, impacts healthspan and lifespan in mice. Our results indicate that Ndufs2 hemizygous mice (Ndufs2+/-) show no overt impairment in aging-related motor function, learning, tissue histology, organismal metabolism, or sensitivity to metformin in a C57BL6/J background. Despite a significant reduction of Ndufs2 mRNA, the mice do not demonstrate a significant decrease in complex I function. However, there are detectable transcriptomic changes in individual cell types and tissues due to loss of one allele of Ndufs2. Our data indicate that a 50% decline in mRNA of the core mitochondrial complex I subunit Ndufs2 is neither beneficial nor detrimental to healthspan.
  17. Cells. 2022 Mar 16. pii: 1010. [Epub ahead of print]11(6):
      Aging is one of the major non-reversible risk factors for several chronic diseases, including cancer, type 2 diabetes, dementia, and cardiovascular diseases (CVD), and it is a key cause of multimorbidity, disability, and frailty (decreased physical activity, fatigue, and weight loss). The underlying cellular mechanisms are complex and consist of multifactorial processes, such as telomere shortening, chronic low-grade inflammation, oxidative stress, mitochondrial dysfunction, accumulation of senescent cells, and reduced autophagy. In this review, we focused on the molecular mechanisms and translational aspects of cardiovascular aging-related inflammation, i.e., inflammaging.
    Keywords:  cardiac inflammaging; microbiome; mitochondrial homeostasis; vascular senescence
  18. Aging Cell. 2022 Mar 22. e13597
      Ageing is a significant risk factor for degeneration of the retina. Müller glia cells (MG) are key for neuronal regeneration, so harnessing the regenerative capacity of MG in the retina offers great promise for the treatment of age-associated blinding conditions. Yet, the impact of ageing on MG regenerative capacity is unclear. Here, we show that the zebrafish retina undergoes telomerase-independent, age-related neurodegeneration but that this is insufficient to stimulate MG proliferation and regeneration. Instead, age-related neurodegeneration is accompanied by MG morphological aberrations and loss of vision. Mechanistically, yes-associated protein (Yap), part of the Hippo signalling, has been shown to be critical for the regenerative response in the damaged retina, and we show that Yap expression levels decline with ageing. Despite this, morphologically and molecularly altered aged MG retain the capacity to regenerate neurons after acute light damage, therefore, highlighting key differences in the MG response to high-intensity acute damage versus chronic neuronal loss in the zebrafish retina.
    Keywords:  Müller glia; Zebrafish; ageing; degeneration; proliferation; regeneration; retina; telomerase
  19. J Nanobiotechnology. 2022 Mar 19. 20(1): 144
      Aged skin wounds heal poorly, resulting in medical, economic, and social burdens posed by nonhealing wounds. Age-related defects in repair are associated with reduced myofibroblasts and dysfunctional extracellular matrix (ECM) deposition. Bidirectional cell-cell communication involving exosome-borne cargo such as micro RNAs (miRs) has emerged as a critical mechanism for wound healing and aged tissue regeneration. Here we report that at the wound edge, aged fibroblasts display reduced migration and differentiation into myofibroblasts, with impaired ECM deposition, when compared with young tissue. Proper activation of fibroblasts to myofibroblasts may alleviate age-related defects in wound healing. Herein, an exosome-guided cell technique was performed to induce effective wound healing. Supplementing wounds with exosomes isolated from young mouse wound-edge fibroblasts (exosomesYoung) significantly improved the abundance of myofibroblasts and wound healing in aged mice and caused fibroblasts to migrate and transition to myofibroblasts in vitro. To determine the underlying mechanism, we found that exosomal transfer of miR-125b to fibroblasts inhibited sirtuin 7 (Sirt7), thus accelerating myofibroblast differentiation and wound healing in aged mice. Notably, after epidermal inhibition of miR-125b or overexpression of Sirt7 in fibroblasts, migration and myofibroblast transition were perturbed. Our findings thus reveal that miR-125b is transferred through exosomes from young fibroblasts to old fibroblasts contributes to promoting fibroblast migration and transition to counteract aging, suggesting a potential avenue for anti-aging interventions in wound healing.
    Keywords:  ECM deposition; Exosome induced microRNA delivery; Fibroblast to myofibroblast transition; Senescence; Wound healing
  20. Microorganisms. 2022 Mar 21. pii: 668. [Epub ahead of print]10(3):
      The term 'old age' generally refers to a period characterized by profound changes in human physiological functions and susceptibility to disease that accompanies the final years of a person's life. Despite the conventional definition of old age as exceeding the age of 65 years old, quantifying aging as a function of life years does not necessarily reflect how the human body ages. In contrast, characterizing biological (or physiological) aging based on functional parameters may better reflect a person's temporal physiological status and associated disease susceptibility state. As such, differentiating 'chronological aging' from 'biological aging' holds the key to identifying individuals featuring accelerated aging processes despite having a young chronological age and stratifying them to tailored surveillance, diagnosis, prevention, and treatment. Emerging evidence suggests that the gut microbiome changes along with physiological aging and may play a pivotal role in a variety of age-related diseases, in a manner that does not necessarily correlate with chronological age. Harnessing of individualized gut microbiome data and integration of host and microbiome parameters using artificial intelligence and machine learning pipelines may enable us to more accurately define aging clocks. Such holobiont-based estimates of a person's physiological age may facilitate prediction of age-related physiological status and risk of development of age-associated diseases.
    Keywords:  aging; biological age; clocks; microbiome; personalized medicine
  21. Int J Mol Sci. 2022 Mar 17. pii: 3232. [Epub ahead of print]23(6):
      Aging can be defined as the progressive deterioration of cellular, tissue, and organismal function over time. Alterations in protein homeostasis, also known as proteostasis, are a hallmark of aging that lead to proteome imbalances and protein aggregation, phenomena that also occur in age-related diseases. Among the various proteostasis regulators, microRNAs (miRNAs) have been reported to play important roles in the post-transcriptional control of genes involved in maintaining proteostasis during the lifespan in several organismal tissues. In this review, we consolidate recently published reports that demonstrate how miRNAs regulate fundamental proteostasis-related processes relevant to tissue aging, with emphasis on the two most studied tissues, brain tissue and skeletal muscle. We also explore an emerging perspective on the role of miRNA regulatory networks in age-related protein aggregation, a known hallmark of aging and age-related diseases, to elucidate potential miRNA candidates for anti-aging diagnostic and therapeutic targets.
    Keywords:  age-related protein aggregation; mammalian tissue aging; miRNA; proteostasis network
  22. Immun Ageing. 2022 Mar 23. 19(1): 16
      BACKGROUND: Amongst other systemic changes, aging leads to an immune dysfunction. On the molecular level, a hallmark of aging is telomere shortening. The functional relevance of telomerase, an enzyme capable of elongating telomeres in T cells upon antigen stimulation, is not fully understood. Studying the impact of telomere shortening on CD4+ T cells and especially Th1 effector function can provide a better understanding on immune dysfunctions in elderly.RESULTS: We investigated T cell numbers and differentiation in telomerase-deficient (mTerc-/-) mice under steady-state conditions and the functional role of telomerase in CD4+ T cells using in vitro stimulation and Th1 polarization protocols by comparing T cells from mTerc-/- and control mice. We report reduced relative CD4+ T cell numbers in blood and secondary lymphoid organs and a relative decline in the naïve T cell population in thymus, blood and spleen of mTerc-/- mice compared to control mice. Importantly, after in vitro polarization, mTerc-/- G3 CD4+ T cells showed higher numbers of IFNγ-producing cells and reduced expression of CD28. Notably, telomerase-deficient T cells were more susceptible to inhibition of Th1 polarization by IL-6 in vitro. These results demonstrate that telomerase deficiency recapitulates several changes of CD4+ T cells seen in aged humans regarding the naïve T cell population, expression of CD28 and cytokine production.
    CONCLUSION: Our data suggest that telomere shortening could play a key role in the aging of T cell immunity, with clinical implications for immune diseases and tumor development and that mTerc-/- mice are a suitable model to study aging-related defects of adaptive immunity.
    Keywords:  Aging; CD4-positive T-lymphocytes; Telomerase; Telomere shortening; Th1 cells
  23. Mech Ageing Dev. 2022 Mar 17. pii: S0047-6374(22)00047-1. [Epub ahead of print]204 111665
      Geroprotection is defined as protection from the adverse effects of aging. The need for geroprotection implies changes towards individually tailored interventions that preserve an individual's independence, physical function, and cognition. Genistein, a phytoestrogen obtained from soya, has been reported to have beneficial properties on age-related diseases such as neurodegenerative and cardiovascular diseases or cancer. Indeed, genistein is a multimodal agent: it acts as a cancer protective agent, promoting apoptosis and cell cycle arrest, and inhibiting angiogenesis and metastasis, but it also acts as an antioxidant, anti-inflammatory, and anti-amyloid-β and autophagy promoter. Altogether, these properties make genistein a possible treatment for the specific aspects of age-related diseases such as hypertension, metabolic diseases, Alzheimer's disease, and osteoporosis.
    Keywords:  Age-related diseases; Aging; Genistein; Geroprotection
  24. Antioxidants (Basel). 2022 Mar 08. pii: 521. [Epub ahead of print]11(3):
      The connection between oxidative stress and common age-related diseases presents an exciting field of research [...].
  25. Aging Cell. 2022 Mar 23. e13584
      Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, associated with the accumulation of misfolded α-synuclein and lysosomal impairment, two events deemed interconnected. Protein aggregation is linked to defects in degradation systems such as the autophagy-lysosomal pathway, while lysosomal dysfunction is partly related to compromised acidification. We have recently proven that acidic nanoparticles (aNPs) can re-acidify lysosomes and ameliorate neurotoxin-mediated dopaminergic neurodegeneration in mice. However, no lysosome-targeted approach has yet been tested in synucleinopathy models in vivo. Here, we show that aNPs increase α-synuclein degradation through enhancing lysosomal activity in vitro. We further demonstrate in vivo that aNPs protect nigral dopaminergic neurons from cell death, ameliorate α-synuclein pathology, and restore lysosomal function in mice injected with PD patient-derived Lewy body extracts carrying toxic α-synuclein aggregates. Our results support lysosomal re-acidification as a disease-modifying strategy for the treatment of PD and other age-related proteinopathies.
    Keywords:  Parkinson's disease; acidic nanoparticles; alpha-synuclein, neurodegeneration, therapeutics; in vivo; lysosomal restoration
  26. Nutrients. 2022 Mar 15. pii: 1232. [Epub ahead of print]14(6):
      Nutrition plastically modulates the epigenetic landscape in various tissues of an organism during life via epigenetic changes. In the present study, to clarify whether this modulation involves RNA methylation, we evaluated global RNA methylation profiles and the expression of writer, reader, and eraser genes, encoding for enzymes involved in the RNA methylation. The study was carried out in the heart, liver, and kidney samples from rats of different ages in response to a low-calorie diet. We found that, although each tissue showed peculiar RNA methylation levels, a general increase in these levels was observed throughout the lifespan as well as in response to the six-month diet. Similarly, a prominent remodeling of the expression of writer, reader, and eraser genes emerged. Our data provide a comprehensive overview of the role exerted by diet on the tissue-specific epigenetic plasticity of RNA according to aging in rats, providing the first evidence that methylation of RNA, similarly to DNA methylation, can represent an effective biomarker of aging. What is more, the fact that it is regulated by nutrition provides the basis for the development of targeted approaches capable of guaranteeing the maintenance of a state of good health.
    Keywords:  RNA methylation; aging; biomarkers; eraser and reader enzymes; low-calorie diet; nutrition; tissue-specificity; writer
  27. Aging (Albany NY). 2022 Mar 05. 14(5): 2020-2024
    Keywords:  growth; mTOR; quasi-programmed aging; reprogramming; sirolimus
  28. Exp Eye Res. 2022 Mar 17. pii: S0014-4835(22)00116-6. [Epub ahead of print] 109035
      Ageing has been defined as a specific individual plasticity and remodeling capacity to the environment' insults and stimuli. The precise physiology of aging is not entirely understood. Several theories have been proposed and included programmed cell death, genetic mutations, the epigenetic clock, wear-and-tear and free radicals. Ocular surface represents a complex morpho-functional unit composed of different tissues that strictly interact to preserve homeostasis and function. Ageing severely disrupts this system by means of inflammaging and immunosenescence, leading to ocular surface failure in older population.
    Keywords:  Ageing; Immunosenescence; Inflammaging; Ocular surface
  29. Aging (Albany NY). 2022 Mar 19. 14(undefined):
      Downregulation of mTOR (mechanistic target of rapamycin) can extend lifespan in multiple species, including mice. Growth hormone receptor knockout mice (GHRKO) and Snell dwarf mice have 40% or greater lifespan increase, and have lower mTORC1 function, which might reflect alteration in mTORC1 components or alteration of upstream proteins that modulate mTOR activity. Here we report reduction of mTORC components DEPTOR and PRAS40 in liver of these long-lived mice; these changes are opposite in direction to those that would be expected to lead to lower mTORC1 function. In contrast, levels of the upstream regulators TSC1 and TSC2 are elevated in GHRKO and Snell liver, kidney and skeletal muscle, and the ratio of phosphorylated TSC2 to total TSC2 is lower in the tissues of the long-lived mutant mice. In addition, knocking down TSC2 in GHRKO fibroblasts reversed the effects of the GHRKO mutation on mTORC1 function. Thus increased amounts of unphosphorylated, active, inhibitory TSC may contribute to lower mTORC1 function in these mice.
    Keywords:  TSC; aging; growth hormone receptor; lifespan extension; mTOR
  30. Ageing Res Rev. 2022 Mar 17. pii: S1568-1637(22)00051-4. [Epub ahead of print]77 101609
      OBJECTIVE: To systematically investigate the relationship between objective measures of physical capacity (e.g., cardio-respiratory fitness or daily step count) and biological age, measured in different ways.DATA SOURCE: PubMed; SCOPUS - Elsevier API; and Web of Science - ISI 1984-present, as well as contextual search engines used to identify additional relevant publications.
    STUDY SELECTION: Cross-sectional and longitudinal studies that assessed the association between objectively measured physical capacity and biological aging in adult individuals (age>18).
    RESULTS: Analysis of 28 studies demonstrated that physical capacity is positively associated with biological aging; the most dominant measures of physical capacity are muscular strength or gait speed. The majority of the studies estimated biological aging by a single methodology - either Leukocyte Telomere Length or DNA methylation levels.
    CONCLUSIONS: This systematic review of the objective physical capacity measures used to estimate aging finds that the current literature is limited insofar as it overlooks the potential contribution of many feasible markers. We recommend measuring physical capacity in the context of aging using a wide range of modifiable behavioral markers, beyond simple muscle strength or simple gait speed. Forming a feasible and diversified method for estimating physical capacity through which it will also be possible to estimate biological aging in wide population studies is essential for the development of interventions that may alleviate the burden of age-related disease.
    Keywords:  Aging; Exercise; Physical activity; Physical fitness
  31. Sci Rep. 2022 Mar 22. 12(1): 4911
      Transfection of tumor suppressor miRNAs such as miR-34a, miR-449a, and miR-16 with DNA damage can regulate apoptosis and senescence in cancer cells. miR-16 has been shown to influence autophagy in cervical cancer. However, the function of miR-34a and miR-449a in autophagy remains unknown. The functional and persistent G1/S checkpoint signaling pathways in HeLa cells via these three miRNAs, either synergistically or separately, remain a mystery. As a result, we present a synthetic Boolean network of the functional G1/S checkpoint regulation, illustrating the regulatory effects of these three miRNAs. To our knowledge, this is the first synthetic Boolean network that demonstrates the advanced role of these miRNAs in cervical cancer signaling pathways reliant on or independent of p53, such as MAPK or AMPK. We compared our estimated probability to the experimental data and found reasonable agreement. Our findings indicate that miR-34a or miR-16 may control senescence, autophagy, apoptosis, and the functional G1/S checkpoint. Additionally, miR-449a can regulate just senescence and apoptosis on an individual basis. MiR-449a can coordinate autophagy in HeLa cells in a synergistic manner with miR-16 and/or miR-34a.