bims-senagi 2021-08-22 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2021–08–22
39 papers selected by
Maria Grazia Vizioli, Mayo Clinic

YAP prevents premature senescence of astrocytes and cognitive decline of Alzheimer's disease through regulating CDK6 signaling.
Cellular Senescence in Idiopathic Pulmonary Fibrosis.
An Insight into Aging, Senescence, and Their Impacts on Wound Healing.
Immunosenescence and inflammaging in the aging process: age-related diseases or longevity?
The senescence-associated secretory phenotype: Fueling a wound that never heals.
Induced senescence of healthy nucleus pulposus cells is mediated by paracrine signaling from TNF-α-activated cells.
Hedgehog dysregulation contributes to tissue-specific inflammaging of resident macrophages.
Epigenetic and senescence markers indicate an accelerated ageing-like state in women with preeclamptic pregnancies.
Induction of Sestrin2 by pterostilbene suppresses ethanol-triggered hepatocyte senescence by degrading CCN1 via p62-dependent selective autophagy.
Downregulation of Cav3.1 T-type Calcium Channel Expression in Age-related Hearing Loss Model.
NAD+ in Alzheimer's Disease: Molecular Mechanisms and Systematic Therapeutic Evidence Obtained in vivo.
TCTP overexpression reverses age-associated telomere attrition by upregulating telomerase activity in mouse oocytes.
Extracellular Vesicles Tell All: how vesicle-mediated cellular communication shapes hematopoietic stem cell biology with increasing age.
Analysis of the dynamic changes in the proportion of immune cells and the proportion of cells with stem cell characteristics in the corresponding immune cell population of C57 mice during the natural aging process.
Epigenetic age prediction.
The killifish visual system as an in vivo model to study brain aging and rejuvenation.
Circulating Pro-inflammatory Exosomes Worsen Stroke Outcomes in Aging.
Frailty and biological age.
Skeletal muscle mitochondrial network dynamics in metabolic disorders and aging.
ZNF768 links oncogenic RAS to cellular senescence.
TGF-β2 and collagen play pivotal roles in the spheroid formation and anti-aging of human dermal papilla cells.
Lycium barbarum polysaccharides in ageing and its potential use for prevention and treatment of osteoarthritis: a systematic review.
p21-Activated kinase 1 (PAK1) in aging and longevity: An overview.
Revelations About Aging and Disease from Unconventional Vertebrate Model Organisms.
GDF11 protects against glucotoxicity-induced mice retinal microvascular endothelial cell dysfunction and diabetic retinopathy disease.
Functional Aging in Male C57BL/6J Mice Across the Life-Span: A Systematic Behavioral Analysis of Motor, Emotional, and Memory Function to Define an Aging Phenotype.
Differential retinoic acid signaling in the hippocampus of aged rats with and without memory impairment.
Prolonged caloric restriction ameliorates age-related atrophy in slow and fast muscle fibers of rat soleus muscle.
The role of mitochondria dysfunction and hepatic senescence in NAFLD development and progression.
Multiple phosphorylation events of the mitochondrial membrane protein, TTM1, regulate cell death during senescence.
Therapeutic effect of Keap1-Nrf2-ARE pathway-related drugs on age-related eye diseases through anti-oxidative stress.
Accumulation of C-terminal cleaved tau is distinctly associated with cognitive deficits, synaptic plasticity impairment, and neurodegeneration in aged mice.
Telomere length: biological marker of cellular vitality, aging, and health-disease process.
Metformin and leucine increase satellite cells and collagen remodeling during disuse and recovery in aged muscle.
Lifelong Exercise in Age Rats Improves Skeletal Muscle Function and MicroRNA Profile.
Lifelong dietary omega-3 fatty acid suppresses thrombotic potential through gut microbiota alteration in aged mice.
Adiponectin inhibits D‑gal‑induced cardiomyocyte senescence via AdipoR1/APPL1.
Fluc-EGFP reporter mice reveal differential alterations of neuronal proteostasis in aging and disease.
Emerging roles of oxidative stress in brain aging and Alzheimer's disease.

Aging Cell. 2021 Aug 20. e13465

YAP prevents premature senescence of astrocytes and cognitive decline of Alzheimer's disease through regulating CDK6 signaling.

Xingxing Xu, Xiya Shen, Jiaojiao Wang, Wenjin Feng, Mianxian Wang, Xuemeng Miao, Qian Wu, Lihao Wu, Xiaoning Wang, Yimin Ma, Shuang Wu, Xiaomei Bao, Wei Wang, Ying Wang, Zhihui Huang.

  Senescent astrocytes accumulate with aging and contribute to brain dysfunction and diseases such as Alzheimer's disease (AD), however, the mechanisms underlying the senescence of astrocytes during aging remain unclear. In the present study, we found that Yes-associated Protein (YAP) was downregulated and inactivated in hippocampal astrocytes of aging mice and AD model mice, as well as in D-galactose and paraquat-induced senescent astrocytes, in a Hippo pathway-dependent manner. Conditional knockout of YAP in astrocytes significantly promoted premature senescence of astrocytes, including reduction of cell proliferation, hypertrophic morphology, increase in senescence-associated β-galactosidase activity, and upregulation of several senescence-associated genes such as p16, p53 and NF-κB, and downregulation of Lamin B1. Further exploration of the underlying mechanism revealed that the expression of cyclin-dependent kinase 6 (CDK6) was decreased in YAP knockout astrocytes in vivo and in vitro, and ectopic overexpression of CDK6 partially rescued YAP knockout-induced senescence of astrocytes. Finally, activation of YAP signaling by XMU-MP-1 (an inhibitor of Hippo kinase MST1/2) partially rescued the senescence of astrocytes and improved the cognitive function of AD model mice and aging mice. Taken together, our studies identified unrecognized functions of YAP-CDK6 pathway in preventing astrocytic senescence in vitro and in vivo, which may provide further insights and new targets for delaying brain aging and aging-related neurodegenerative diseases such as AD.

Keywords:  CDK6; YAP; alzheimer's disease; astrocytes; senescence

DOI:  https://doi.org/10.1111/acel.13465
Curr Mol Biol Rep. 2021 Aug 12. 1-10

Cellular Senescence in Idiopathic Pulmonary Fibrosis.

D L Kellogg, D L Kellogg, N Musi, A M Nambiar.

  Cellular senescence (CS) is increasingly implicated in the etiology of age-related diseases. While CS can facilitate physiological processes such as tissue repair and wound healing, senescent cells also contribute to pathophysiological processes involving macromolecular damage and metabolic dysregulation that characterize multiple morbid and prevalent diseases, including Alzheimer's disease, osteoarthritis, atherosclerotic vascular disease, diabetes mellitus, and idiopathic pulmonary fibrosis (IPF). Preclinical studies targeting senescent cells and the senescence-associated secretory phenotype (SASP) with "senotherapeutics" have demonstrated improvement in age-related morbidity associated with these disease states. Despite promising results from these preclinical trials, few human clinical trials have been conducted. A first-in-human, open-label, pilot study of the senolytic combination of dasatinib and quercetin (DQ) in patients with IPF showed improved physical function and mobility. In this review, we will discuss our current understanding of cellular senescence, its role in age-associated diseases, with a specific focus on IPF, and potential for senotherapeutics in the treatment of fibrotic lung diseases.

Keywords:  Cellular senescence; Idiopathic pulmonary fibrosis; Senolytics; Senomorphics

DOI:  https://doi.org/10.1007/s40610-021-00145-4
Adv Geriatr Med Res. 2021 ;pii: e210017. [Epub ahead of print]3(3):

An Insight into Aging, Senescence, and Their Impacts on Wound Healing.

Rex Jeya Rajkumar Samdavid Thanapaul, Maria Shvedova, Grace Haeun Shin, Daniel S Roh.

  Cellular senescence has been found to have beneficial roles in development, tissue regeneration, and wound healing. However, in aging senescence increases, and the ability to properly repair and heal wounds significantly declines across multiple tissues. This age-related accumulation of senescent cells may cause loss of tissue homeostasis leading to dysregulation of normal and timely wound healing processes. The delays in wound healing of aging have widespread clinical and economic impacts, thus novel strategies to improve wound healing in aging are needed and targeting senescence may be a promising area.

Keywords:  aging; senescence; senolytics; senomorphics; wound healing

DOI:  https://doi.org/10.20900/agmr20210017
Ageing Res Rev. 2021 Aug 12. pii: S1568-1637(21)00169-0. [Epub ahead of print] 101422

Immunosenescence and inflammaging in the aging process: age-related diseases or longevity?

Aurelia Santoro, Elisa Bientinesi, Daniela Monti.

  During aging the immune system (IS) undergoes remarkable changes that collectively are known as immunosenescence. It is a multifactorial and dynamic phenomenon that affects both natural and acquired immunity and plays a critical role in most chronic diseases in older people. For a long time, immunosenescence has been considered detrimental because it may lead to a low-grade, sterile chronic inflammation we proposed to call "inflammaging" and a progressive reduction in the ability to trigger effective antibody and cellular responses against infections and vaccinations. Recently, many scientists revised this negative meaning because it can be considered an essential adaptation/remodeling resulting from the lifelong immunological biography of single individuals from an evolutionary perspective. Inflammaging can be considered an adaptive process because it can trigger an anti-inflammatory response to counteract the age-related pro-inflammatory environment. Centenarians represent a valuable model to study the beneficial changes occurring in the IS with age. These extraordinary individuals reached the extreme limits of human life by slowing down the aging process and, in most cases, delaying, avoiding or surviving the major age-associated diseases. They indeed show a complex and heterogeneous phenotype determined by an improved ability to adapt and remodel in response to harmful stimuli. This review aims to point out the intimate relationship between immunosenescence and inflammaging and how these processes impact unsuccessful aging rather than longevity. We also describe the gut microbiota age-related changes as one of the significant triggers of inflammaging and the sex/gender differences in the immune system of the elderly, contributing to the sex/gender disparity in terms of epidemiology, pathophysiology, symptoms and severity of age-related diseases. Finally, we discuss how these phenomena could influence the susceptibility to COVID-19 infection.

Keywords:  Aging; COVID-19; Centenarians; Immunosenescence; Inflammaging; Innate immunity; Longevity

DOI:  https://doi.org/10.1016/j.arr.2021.101422
Mech Ageing Dev. 2021 Aug 16. pii: S0047-6374(21)00133-0. [Epub ahead of print] 111561

The senescence-associated secretory phenotype: Fueling a wound that never heals.

Tanya Pulido, Michael C Velarde, Fatouma Alimirah.

  Wound healing is impaired with advanced age and certain chronic conditions, such as diabetes and obesity. Moreover, common cancer treatments, including chemotherapy and radiation, can cause unintended tissue damage and impair wound healing. Available wound care treatments are not always effective, as some wounds fail to heal or recur after treatment. Hence, a more thorough understanding of the pathophysiology of chronic, nonhealing wounds may offer new ideas for the development of effective wound care treatments. Cancers are sometimes referred to as wounds that never heal, sharing mechanisms similar to wound healing. We describe in this review how cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to chronic wounds versus cancer.

Keywords:  Cancer; Cellular senescence; Chronic wounds; Inflammation; Senescence-associated secretory phenotype; Wound healing

DOI:  https://doi.org/10.1016/j.mad.2021.111561
FASEB J. 2021 Sep;35(9): e21795

Induced senescence of healthy nucleus pulposus cells is mediated by paracrine signaling from TNF-α-activated cells.

Sajjad Ashraf, Paul Santerre, Rita Kandel.

  Intervertebral disc degeneration is an irreversible process associated with accumulation of senescent nucleus pulposus (NP) cells. This study investigates the hypothesis that Tumor necrosis factor-α (TNF-α)-treated senescent NP cells propagate senescence of neighboring healthy cells via a paracrine effect that involves p-Stat3 signaling and the cytokine interleukin-6 (IL-6). NP cells isolated from bovine caudal intervertebral disc (IVD) were treated with TNF-α to induce senescence which was confirmed by demonstrating upregulation of senescence-associated β-galactosidase and p16. This was correlated with downregulation of NP-associated markers, Aggrecan, Col2A1, and Sox9. Direct contact and non-contact co-culture of healthy and senescent cells showed that TNF-α-treated cells increased the senescence in healthy cells via a paracrine effect. The senescent cells have a secretory phenotype as indicated by increased gene and protein levels of IL-6. Phosphorylated Signal Transducer and Activator of Transcription 3 (pStat3) levels were also high in treated cells and appeared to upregulate IL-6 as inhibition of Stat3 phosphorylation by StatticV downregulated IL-6 mRNA expression in cells and protein levels in the culture media. All trans retinoic acid, an IL-6 inhibitor, also decreased the secretion of IL-6 and reduced the paracrine effect of senescent cells on healthy cells. Decreased pStat3 levels and inhibition of IL-6 secretion did not fully restore NP gene expression of Col2A1 but importantly, appeared to cause senescent cells to undergo apoptosis and cell death. This study demonstrated the paracrine effect of senescent NP cells which involves Stat3 and IL-6 and may explain why senescent NP cells accumulate in IVD with age. The role of pSTAT3 and IL-6 in mediating NP senescence requires further study as it may be a novel strategy for modulating the senescent-inducing effects of TNF-α.

Keywords:  IL-6; STAT3; TNF-α; intervertebral disc; paracrine effect; senescence

DOI:  https://doi.org/10.1096/fj.202002201R
Aging (Albany NY). 2021 Aug 14. 13(undefined):

Hedgehog dysregulation contributes to tissue-specific inflammaging of resident macrophages.

Mahamat Babagana, Kyu-Seon Oh, Sayantan Chakraborty, Alicja Pacholewska, Mohammad Aqdas, Myong-Hee Sung.

  Age-associated low-grade sterile inflammation, commonly referred to as inflammaging, is a recognized hallmark of aging, which contributes to many age-related diseases. While tissue-resident macrophages are innate immune cells that secrete many types of inflammatory cytokines in response to various stimuli, it is not clear whether they have a role in driving inflammaging. Here we characterized the transcriptional changes associated with physiological aging in mouse resident macrophage populations across different tissues and sexes. Although the age-related transcriptomic signatures of resident macrophages were strikingly tissue-specific, the differentially expressed genes were collectively enriched for those with important innate immune functions such as antigen presentation, cytokine production, and cell adhesion. The brain-resident microglia had the most wide-ranging age-related alterations, with compromised expression of tissue-specific genes and relatively exaggerated responses to endotoxin stimulation. Despite the tissue-specific patterns of aging transcriptomes, components of the hedgehog (Hh) signaling pathway were decreased in aged macrophages across multiple tissues. In vivo suppression of Hh signaling in young animals increased the expression of pro-inflammatory cytokines, while in vitro activation of Hh signaling in old macrophages, in turn, suppressed the expression of these inflammatory cytokines. This suggests that hedgehog signaling could be a potential intervention axis for mitigating age-associated inflammation and related diseases. Overall, our data represent a resourceful catalog of tissue-specific and sex-specific transcriptomic changes in resident macrophages of peritoneum, liver, and brain, during physiological aging.

Keywords:  aging; inflammaging; inflammation; tissue-resident macrophages; transcriptomics

DOI:  https://doi.org/10.18632/aging.203422
EBioMedicine. 2021 Aug 11. pii: S2352-3964(21)00329-7. [Epub ahead of print]70 103536

Epigenetic and senescence markers indicate an accelerated ageing-like state in women with preeclamptic pregnancies.

Sonja Suvakov, Ranine Ghamrawi, Hajrunisa Cubro, Haitao Tu, Wendy M White, Yvonne S Butler Tobah, Natasa M Milic, Joseph P Grande, Julie M Cunningham, Fouad T Chebib, Larissa G P Langhi Prata, Yi Zhu, Tamara Tchkonia, James L Kirkland, Karl A Nath, Aleksandar Milosavljevic, Vesna D Garovic.

   BACKGROUND: Preeclampsia is a pregnancy-specific hypertensive disorder characterized by proteinuria and/or multisystem involvement. Disease-specific therapy has yet to be developed due to the lack of understanding of underlying mechanism(s). We postulate that accelerated ageing in general, and particularly cellular senescence, play a role in its pathophysiology.
METHODS: We compared women with preeclampsia vs. normotensive pregnancies with respect to epigenetic markers of ageing and markers of senescence in tissues/organs affected by preeclampsia (blood, urine, adipose tissue, and kidney).
FINDINGS: We demonstrate that preeclamptic compared to normotensive pregnant women: (i) undergo accelerated epigenetic ageing during pregnancy, as demonstrated by an "epigenetic clock"; (ii) exhibit higher levels/expression of senescence-associated secretory phenotype factors in blood and adipose tissue; (iii) display increased expression of p16INK4A in adipose tissue and renal sections, and (iv) demonstrate decreased levels of urinary α-Klotho (an anti-ageing protein) at the time of delivery. Finally, we provide data indicating that pre-treatment with dasatinib, a senolytic agent, rescues the angiogenic potential of mesenchymal stem cells (MSC) obtained from preeclamptic pregnancies, and promotes angiogenesis, even under pro-inflammatory conditions.
INTERPRETATION: Taken together, our results identify senescence as one of the mechanisms underpinning the pathophysiology of preeclampsia. Therapeutic strategies that target senescent cells may offer novel mechanism-based treatments for preeclampsia.
FUNDING: This work was supported by NIH grants, R01 HL136348, R37 AG013925, P01 AG062413, R01 DK11916, generous gifts from the Connor Fund, Robert J. and Theresa W. Ryan and from The George G. Beasley family, the Noaber Foundation, and the Henry and Emma Meyer Professorship in Molecular Genetics.

Keywords:  ageing; epigenetic clock; preeclampsia; senescence

DOI:  https://doi.org/10.1016/j.ebiom.2021.103536
Cell Biol Toxicol. 2021 Aug 17.

Induction of Sestrin2 by pterostilbene suppresses ethanol-triggered hepatocyte senescence by degrading CCN1 via p62-dependent selective autophagy.

Yiming Jiang, Ying Zhou, Wenxuan Xu, Xinqi Wang, Huanhuan Jin, Xiaofeng Bao, Chunfeng Lu.

  Hepatocyte senescence is a key event participating in the progression of alcoholic liver disease. Autophagy is a critical biological process that controls cell fates by affecting cell behaviors like senescence. Pterostilbene is a natural compound with hepatoprotective potential; however, its implication for alcoholic liver disease was not understood. This study was aimed to investigate the therapeutic effect of pterostilbene on alcoholic liver disease and elucidate the potential mechanism. Our results showed that pterostilbene alleviated ethanol-triggered hepatocyte damage and senescence. Intriguingly, pterostilbene decreased the protein abundance of cellular communication network factor 1 (CCN1) in ethanol-exposed hepatocytes, which was essential for pterostilbene to execute its anti-senescent function. In vivo studies verified the anti-senescent effect of pterostilbene on hepatocytes of alcohol-intoxicated mice. Pterostilbene also relieved senescence-associated secretory phenotype (SASP), redox imbalance, and steatosis by suppressing hepatic CCN1 expression. Mechanistically, pterostilbene-forced CCN1 reduction was dependent on posttranscriptional regulation via autophagy machinery but not transcriptional regulation. To be specific, pterostilbene restored autophagic flux in damaged hepatocytes and activated p62-mediated selective autophagy to recognize and lead CCN1 to autolysosomes for degradation. The protein abundance of Sestrin2 (SESN2), a core upstream modulator of autophagy pathway, was decreased in ethanol-administrated hepatocytes but rescued by co-treatment with pterostilbene. Induction of SESN2 protein by pterostilbene rescued ethanol-triggered autophagic dysfunction in hepatocytes, which then reduced senescence-associated markers, postponed hepatocyte senescence, and relieved alcohol-caused liver injury and inflammation. In conclusion, this work discovered a novel compound pterostilbene with therapeutic implications for alcoholic liver disease and uncover its underlying mechanism.

Keywords:  Alcoholic liver disease; Autophagy; CCN1; Hepatocyte; Pterostilbene; Senescence; Sestrin2

DOI:  https://doi.org/10.1007/s10565-021-09635-8
Curr Med Sci. 2021 Aug;41(4): 680-686

Downregulation of Cav3.1 T-type Calcium Channel Expression in Age-related Hearing Loss Model.

Chun-Chen Pan, Zhi-Hui Du, Yi Zhao, Han-Qi Chu, Jin-Wu Sun.

   OBJECTIVE: Age-related hearing loss (AHL), characterized by degeneration of cochlea structures, is the most common sensory disorder among the elderly worldwide. The calcium channel is considered to contribute to normal hearing. However, the role of the T-type voltage-activated calcium channel, Cav3.1, remains unclear in AHL. Here, we investigate the age-related change of Cav3.1 expression in the cochlea and D-gal-induced senescent HEI-OC1 cells.
METHODS: Cochleae from C57BL/6 mice at 2 months and 12 months of age were assessed. Senescence in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells was induced by D-gal treatment. The immunofluorescence technique was employed to investigate the distribution of Cav3.1 in vivo and in vitro. Quantitative assessment was achieved by Western blotting and real-time PCR.
RESULTS: In comparison with 2-month-old animals, 12-month old C57BL/6 mice exhibited great loss of hair cells and elevated auditory brainstem threshold. The Cav3.1 was located in hair cells, spiral ganglion cells, lateral walls, and the expression of Cav3.1 protein and mRNA decreased in the aged cochleae. D-gal-induced senescence assay confirmed the down-regulation of Cav3.1 expression in senescent HEI-OC1 cells.
CONCLUSION: Our results show that age-related down-regulated expression of Cav3.1 in the cochleae is associated with AHL and may contribute to the pathogenesis of AHL.

Keywords:  C57BL/6 mouse; HEI-OC1; cochlea; presbycusis

DOI:  https://doi.org/10.1007/s11596-021-2416-0
Front Cell Dev Biol. 2021 ;9 668491

NAD+ in Alzheimer's Disease: Molecular Mechanisms and Systematic Therapeutic Evidence Obtained in vivo.

Xinshi Wang, Hai-Jun He, Xi Xiong, Shuoting Zhou, Wen-Wen Wang, Liang Feng, Ruiyu Han, Cheng-Long Xie.

  Mitochondria in neurons generate adenosine triphosphate (ATP) to provide the necessary energy required for constant activity. Nicotinamide adenine dinucleotide (NAD+) is a vital intermediate metabolite involved in cellular bioenergetics, ATP production, mitochondrial homeostasis, and adaptive stress responses. Exploration of the biological functions of NAD+ has been gaining momentum, providing many crucial insights into the pathophysiology of age-associated functional decline and diseases, such as Alzheimer's disease (AD). Here, we systematically review the key roles of NAD+ precursors and related metabolites in AD models and show how NAD+ affects the pathological hallmarks of AD and the potential mechanisms of action. Advances in understanding the molecular roles of NAD+-based neuronal resilience will result in novel approaches for the treatment of AD and set the stage for determining whether the results of exciting preclinical trials can be translated into the clinic to improve AD patients' phenotypes.

Keywords:  Alzheimer’s disease; NAD+; NAD+ precursors; aging; molecular mechanisms

DOI:  https://doi.org/10.3389/fcell.2021.668491
J Cell Physiol. 2021 Aug 18.

TCTP overexpression reverses age-associated telomere attrition by upregulating telomerase activity in mouse oocytes.

Hyuk-Joon Jeon, Minsung Kang, Jae-Sung Kim, Jeong Su Oh.

  A prolonged time span between ovulation and fertilization can cause postovulatory aging of oocytes, which impairs oocyte quality and subsequent embryo development. Telomere attrition has long been considered as the primary hallmark of aging or the cause of age-associated diseases. However, the status of telomere and its regulation during postovulatory oocyte aging are poorly understood. Here we found that oocytes experience telomere shortening during postovulatory aging, although they have the capacity to maintain telomere length. However, translationally controlled tumor protein (TCTP) overexpression could reverse age-associated telomere shortening by upregulating telomerase activity in mouse oocytes. Telomere length in mature oocytes gradually decreased with postovulatory aging, which was associated with a marked reduction in TRF1 expression, decreased telomerase activity, and decreased homologous combination (HR)-based alternative lengthening of telomeres (ALT) with a concomitant increase in oxidative stress. Surprisingly, however, overexpression of TCTP led to a remarkable increase in telomere length during postovulatory aging. Notably, neither TRF1 nor BRCA1 level was altered by TCTP overexpression. Moreover, TCTP-mediated telomere lengthening was not blocked by HR inhibition. In striking contrast, telomerase activity, as well as TERT and TERC levels, increased after TCTP overexpression. Importantly, unlike the chromosome-wide distribution of endogenous TCTP, overexpressed TCTP was ectopically localized at telomeres, implying that TCTP overexpression is required to increase telomerase activity. Collectively, our results demonstrate that TCTP prevents telomere attrition during postovulatory aging by upregulating telomerase activity in mouse oocytes.

Keywords:  TCTP; oocyte; postovulatory aging; telomerase; telomere

DOI:  https://doi.org/10.1002/jcp.30557
Exp Hematol. 2021 Aug 15. pii: S0301-472X(21)00284-8. [Epub ahead of print]

Extracellular Vesicles Tell All: how vesicle-mediated cellular communication shapes hematopoietic stem cell biology with increasing age.

Isabelle Grenier-Pleau, Sheela A Abraham.

Extracellular vesicles (EVs), small lipid bilayer particles containing biologically important cargo, impart regulatory changes in target cells. Despite the importance EVs play in cellular communication, there remains a gap in understanding with respect to how EVs influence HSC fate, and in turn, how aging and longevity are impacted. This review summarizes the current literature surrounding how age-altered intercellular communication mediated by extracellular vesicles (EVs) influences HSC biology.

DOI: https://doi.org/10.1016/j.exphem.2021.08.004
Immunol Res. 2021 Aug 20.

Analysis of the dynamic changes in the proportion of immune cells and the proportion of cells with stem cell characteristics in the corresponding immune cell population of C57 mice during the natural aging process.

Jing Luan, Hao Xu, Zhang Jin, Hua Guan, Xingchun Gao, Xingchun Gou, Lixian Xu.

  The aging of the immune system is not only an inevitable result but also an important cause of physical aging. The aging of the immune system is rooted in the aging of hematopoietic cells (HSCs), which manifests as decreasing functionality of the adaptive immune system and the innate immune system. C57BL/6 mice of different ages were collected in this study to better understand the changes in the structures of the innate and adaptive immune systems in individuals of different ages and the distribution and changes in immune cells with stem cell properties. The immune cells of the innate and adaptive immune systems, including DCs, monocytes, macrophages, CD4+ T lymphocytes, CD8+ T lymphocytes, and B lymphocytes, were assessed, and the proportions of cells with stem cell properties among these immune cell populations were also tested. Overall, immune cells in the peripheral blood, spleen, and bone marrow of mice exhibit certain regular properties with increasing age. The trend of changes in immune cells in different immune organs differs with age. The changes in lymphocytes in the peripheral blood are more sensitive. Their proportions increase slowly with age and then decrease rapidly to a very low level (less than 5%) after a certain point (9 or 13 months old). Nine to 13 months of age is the most critical time point for assessing changes in the immune system of mice and the most critical time point for detecting changes in the proportion of stem cells. After 13 months of age, the balance and stability of stem cells in mice are disrupted, and animals begin to age rapidly. The ratio of Ly6A to E+CD117+ cells in the peripheral blood, particularly lymphocytes involved in adaptive immunity, represents a specific marker for predicting immune senescence and body senescence.

Keywords:  Aging; Biomarkers; CD117; HSC; Immunosenescence; Ly6A/E

DOI:  https://doi.org/10.1007/s12026-021-09229-w
Aging Cell. 2021 Aug 20. e13452

Epigenetic age prediction.

Daniel J Simpson, Tamir Chandra.

  Advanced age is the main common risk factor for cancer, cardiovascular disease and neurodegeneration. Yet, more is known about the molecular basis of any of these groups of diseases than the changes that accompany ageing itself. Progress in molecular ageing research was slow because the tools predicting whether someone aged slowly or fast (biological age) were unreliable. To understand ageing as a risk factor for disease and to develop interventions, the molecular ageing field needed a quantitative measure; a clock for biological age. Over the past decade, a number of age predictors utilising DNA methylation have been developed, referred to as epigenetic clocks. While they appear to estimate biological age, it remains unclear whether the methylation changes used to train the clocks are a reflection of other underlying cellular or molecular processes, or whether methylation itself is involved in the ageing process. The precise aspects of ageing that the epigenetic clocks capture remain hidden and seem to vary between predictors. Nonetheless, the use of epigenetic clocks has opened the door towards studying biological ageing quantitatively, and new clocks and applications, such as forensics, appear frequently. In this review, we will discuss the range of epigenetic clocks available, their strengths and weaknesses, and their applicability to various scientific queries.

Keywords:  ageing; composite predictors; epigenetic clocks; minimised clocks; mortality

DOI:  https://doi.org/10.1111/acel.13452
NPJ Aging Mech Dis. 2021 Aug 17. 7(1): 22

The killifish visual system as an in vivo model to study brain aging and rejuvenation.

Sophie Vanhunsel, Steven Bergmans, An Beckers, Isabelle Etienne, Jolien Van Houcke, Eve Seuntjens, Lut Arckens, Lies De Groef, Lieve Moons.

Worldwide, people are getting older, and this prolonged lifespan unfortunately also results in an increased prevalence of age-related neurodegenerative diseases, contributing to a diminished life quality of elderly. Age-associated neuropathies typically include diseases leading to dementia (Alzheimer's and Parkinson's disease), as well as eye diseases such as glaucoma and age-related macular degeneration. Despite many research attempts aiming to unravel aging processes and their involvement in neurodegeneration and functional decline, achieving healthy brain aging remains a challenge. The African turquoise killifish (Nothobranchius furzeri) is the shortest-lived reported vertebrate that can be bred in captivity and displays many of the aging hallmarks that have been described for human aging, which makes it a very promising biogerontology model. As vision decline is an important hallmark of aging as well as a manifestation of many neurodegenerative diseases, we performed a comprehensive characterization of this fish's aging visual system. Our work reveals several aging hallmarks in the killifish retina and brain that eventually result in a diminished visual performance. Moreover, we found evidence for the occurrence of neurodegenerative events in the old killifish retina. Altogether, we introduce the visual system of the fast-aging killifish as a valuable model to understand the cellular and molecular mechanisms underlying aging in the vertebrate central nervous system. These findings put forward the killifish for target validation as well as drug discovery for rejuvenating or neuroprotective therapies ensuring healthy aging.

DOI: https://doi.org/10.1038/s41514-021-00077-4
Circ Res. 2021 Aug 17.

Circulating Pro-inflammatory Exosomes Worsen Stroke Outcomes in Aging.

Hongxia Zhang, Siyang Lin, Christopher L McElroy, Brian Wang, Dana Jin, Victor V Uteshev, Kunlin Jin.

Rationale: The systemic inflammatory milieu plays an important role in the age-related decline in functional integrity, but its contribution to age-related disease (e.g., stroke) remains largely unknown. Objective: To determine the role of systemic inflammatory milieu in ischemic stroke. Methods and Results: Here, we report that systemic administration of serum exosomes from young rats (Y-exo) into aged ischemic rats improved short- and long-term functional outcomes after ischemic stroke and reduced synaptic loss. By contract, similar injections of serum exosomes from aged rats (O-exo) into aged ischemic rats worsened sensorimotor deficits through exacerbation of synaptic dysfunction due to excessive microglial phagoptosis (primary phagocytosis). Our proteomic analysis further revealed that the expression of CD46, a C3b/C4b-inactivating factor, was higher in Y-exo, compared to O-exo. Whereas the prevalence of pro-inflammatory mediators (C1q, C3a and C3b) in serum exosomes increased with age. Microglial expression of C3a/b and C3aR increased after O-exo treatment, compared with Y-exo and vehicle groups. Administration of a selective C3aR inhibitor or microglial depletion attenuated synaptic dysfunction associated with O-exo treatment and improved post-stroke functional recovery. Conclusions: Our data suggest that the levels of pro-inflammatory mediators in serum exosomes increase with age and are associated with worsened stroke outcomes through excessive C3aR-dependent microglial phagoptosis. Modulation of this process may serve as a promising therapy for stroke and other age-related brain disorders.

DOI: https://doi.org/10.1161/CIRCRESAHA.121.318897
Ann Geriatr Med Res. 2021 Aug 17.

Frailty and biological age.

Lixin Ji, S Michal Jazwinski, Sangkyu Kim.

  A reliable model of biological age is instrumental in geriatrics and gerontology. It should account for heterogeneity and plasticity of aging. It should also accurately predict aging-related adverse outcomes. Epigenetic age models are based on DNA methylation levels of selected genomic sites. Some of the epigenetic age models are significant predictors of mortality and healthy/unhealthy aging. However, biological function of DNA methylation at the selected sites is yet to be determined. Frailty is viewed as a syndrome resulting from declined physiological reserve and resilience. The frailty index is a probability-based extension of the frailty concept. Simply being the proportion of health deficits, the frailty index quantifies the progression of unhealthy aging. The frailty index is the best predictor of mortality. It is associated with various biological factors, providing insight into biological processes of aging. Investigation of multiomics factors associated with the frailty index will provide further insight.

Keywords:  DNA methylation; aging; biological; epigenetic; frailty

DOI:  https://doi.org/10.4235/agmr.21.0080
Trends Mol Med. 2021 Aug 17. pii: S1471-4914(21)00198-2. [Epub ahead of print]

Skeletal muscle mitochondrial network dynamics in metabolic disorders and aging.

Ciarán E Fealy, Lotte Grevendonk, Joris Hoeks, Matthijs K C Hesselink.

  With global demographics trending towards an aging population, the numbers of individuals with an age-associated loss of independence is increasing. A key contributing factor is loss of skeletal muscle mitochondrial, metabolic, and contractile function. Recent advances in imaging technologies have demonstrated the importance of mitochondrial morphology and dynamics in the pathogenesis of disease. In this review, we examine the evidence for altered mitochondrial dynamics as a mechanism in age and obesity-associated loss of skeletal muscle function, with a particular focus on the available human data. We highlight some of the areas where more data are needed to identify the specific mechanisms connecting mitochondrial morphology and skeletal muscle dysfunction.

Keywords:  aging; metabolic disease; mitochondria; mitochondrial dynamics; sarcopenia

DOI:  https://doi.org/10.1016/j.molmed.2021.07.013
Nat Commun. 2021 08 17. 12(1): 4841

ZNF768 links oncogenic RAS to cellular senescence.

Romain Villot, Audrey Poirier, Inan Bakan, Karine Boulay, Erlinda Fernández, Romain Devillers, Luciano Gama-Braga, Laura Tribouillard, Andréanne Gagné, Éma Duchesne, Danielle Caron, Jean-Sébastien Bérubé, Jean-Christophe Bérubé, Yan Coulombe, Michèle Orain, Yves Gélinas, Stéphane Gobeil, Yohan Bossé, Jean-Yves Masson, Sabine Elowe, Steve Bilodeau, Venkata Manem, Philippe Joubert, Frédérick A Mallette, Mathieu Laplante.

RAS proteins are GTPases that lie upstream of a signaling network impacting cell fate determination. How cells integrate RAS activity to balance proliferation and cellular senescence is still incompletely characterized. Here, we identify ZNF768 as a phosphoprotein destabilized upon RAS activation. We report that ZNF768 depletion impairs proliferation and induces senescence by modulating the expression of key cell cycle effectors and established p53 targets. ZNF768 levels decrease in response to replicative-, stress- and oncogene-induced senescence. Interestingly, ZNF768 overexpression contributes to bypass RAS-induced senescence by repressing the p53 pathway. Furthermore, we show that ZNF768 interacts with and represses p53 phosphorylation and activity. Cancer genomics and immunohistochemical analyses reveal that ZNF768 is often amplified and/or overexpressed in tumors, suggesting that cells could use ZNF768 to bypass senescence, sustain proliferation and promote malignant transformation. Thus, we identify ZNF768 as a protein linking oncogenic signaling to the control of cell fate decision and proliferation.

DOI: https://doi.org/10.1038/s41467-021-24932-w
Aging (Albany NY). 2021 Aug 17. 13(undefined):

TGF-β2 and collagen play pivotal roles in the spheroid formation and anti-aging of human dermal papilla cells.

Hyunju Kim, Nahyun Choi, Doo Yeong Kim, So Yoon Kim, Seung Yong Song, Jong-Hyuk Sung.

  Dermal papilla cells (DPCs) tend to aggregate both in vitro and in vivo, which increases the hair inductivity of DPCs. However, the underlying mechanism of spheroid formation is unknown. We investigated whether collagen expression in human DPCs (hDPCs) is involved in the spheroid formation and hair inductivity of hDPCs and further examined the underlying molecular mechanism of collagen upregulation. The expression of diverse collagens, such as COL13A1 and COL15A1, was upregulated in three dimensional (3D)-cultured or intact DPCs, compared to 2D-cultured hDPCs. This collagen expression was a downregulated in aged hair follicle, and aged DPCs were difficult to aggregate. Blocking of COL13A1 and COL15A1 by small interfering RNA reduced aggregation, while induced senescence of hDPCs in vitro. Further, transforming growth factor-β2 (TGF-β2) expression decreases with aging, and is involved in regulating the expression of COL13A1 and COL15A1. Addition of recombinant TGF-β2 delayed cellular senescence, and recovered spheroid formation in aged hDPCs by upregulating collagen levels. On the contrary, knock-out of TGF-β2 induced the aging of DPCs, and inhibited spheroid formation. These results suggested that COL13A1 and COL15A1 expression is downregulated with aging in DPCs, and upregulation of collagen by TGF-β2 induces the spheroid formation of DPCs. Therefore, TGF-β2 supplement in DPC culture medium could enhance the maintenance and hair inductivity of DPCs.

Keywords:  TGF-beta2; aggregation; anti-aging; collagen; human dermal papilla cells

DOI:  https://doi.org/10.18632/aging.203419
BMC Complement Med Ther. 2021 Aug 17. 21(1): 212

Lycium barbarum polysaccharides in ageing and its potential use for prevention and treatment of osteoarthritis: a systematic review.

Junguo Ni, Manting Au, Hangkin Kong, Xinluan Wang, Chunyi Wen.

   BACKGROUND: Lycium barbarum polysaccharide (LBP), the most abundant functional component of wolfberry, is considered a potent antioxidant and an anti-ageing substance. This review aims to outline the hallmarks of ageing in the pathogenesis of osteoarthritis (OA), followed by the current understanding of the senolytic effect of LBP and its potential use in the prevention and treatment of OA. This will be discussed through the lens of molecular biology and herbal medicine.
METHODS: A literature search was performed from inception to March 2020 using following keywords: "Lycium barbarum polysaccharide", "DNA damage", antioxidant, anti-apoptosis, anti-inflammation, anti-ageing, osteoarthritis, chondrocytes, fibroblasts, osteoblasts, osteoclasts, and "bone mesenchymal stem cell". The initial search yielded 2287 papers, from which 35 studies were selected for final analysis after screening for topic relevancy by the authors.
RESULTS: In literature different in vitro and in vivo ageing models are used to demonstrate LBP's ability to reduce oxidative stress, restore mitochondrial function, mitigate DNA damage, and prevent cellular senescence. All the evidence hints that LBP theoretically attenuates senescent cell accumulation and suppresses the senescence-associated secretory phenotype as observed by the reduction in pro-inflammatory cytokines, like interleukin-1beta, and matrix-degrading enzymes, such as MMP-1 and MMP-13. However, there remains a lack of evidence on the disease-modifying effect of LBP in OA, although its chondroprotective, osteoprotective and anti-inflammatory effects were reported.
CONCLUSION: Our findings strongly support further investigations into the senolytic effect of LBP in the context of age-related OA.

Keywords:  Cellular senescence; Lycium Barbarum polysaccharides; Mitochondrial dysfunction; Osteoarthritis; Reactive oxidative species

DOI:  https://doi.org/10.1186/s12906-021-03385-0
Ageing Res Rev. 2021 Aug 12. pii: S1568-1637(21)00190-2. [Epub ahead of print]71 101443

p21-Activated kinase 1 (PAK1) in aging and longevity: An overview.

Mohankumar Amirthalingam, Sundararaj Palanisamy, Shinkichi Tawata.

  The p21-activated kinases (PAKs) belong to serine/threonine kinases family, regulated by ∼21 kDa small signaling G proteins RAC1 and CDC42. The mammalian PAK family comprises six members (PAK1-6) that are classified into two groups (I and II) based on their domain architecture and regulatory mechanisms. PAKs are implicated in a wide range of cellular functions. PAK1 has recently attracted increasing attention owing to its involvement in oncogenesis, tumor progression, and metastasis as well as several life-limiting diseases and pathological conditions. In Caenorhabditis elegans, PAK1 functions limit the lifespan under basal conditions by inhibiting forkhead transcription factor DAF-16. Interestingly, PAK depletion extended longevity and attenuated the onset of age-related phenotypes in a premature-aging mouse model and delayed senescence in mammalian fibroblasts. These observations implicate PAKs as not only oncogenic but also aging kinases. Therefore, PAK-targeting genetic and/or pharmacological interventions, particularly PAK1-targeting, could be a viable strategy for developing cancer therapies with relatively no side effects and promoting healthy longevity. This review describes PAK family proteins, their biological functions, and their role in regulating aging and longevity using C. elegans. Moreover, we discuss the effect of small-molecule PAK1 inhibitors on the lifespan and healthspan of C. elegans.

Keywords:  Caenorhabditis elegans; DAF-16/FOXO; Longevity; PAK1; RAC1/CDC42; p21-Activated kinases

DOI:  https://doi.org/10.1016/j.arr.2021.101443
Annu Rev Genet. 2021 Aug 20.

Revelations About Aging and Disease from Unconventional Vertebrate Model Organisms.

Yang Zhao, Andrei Seluanov, Vera Gorbunova.

Aging is a major risk factor for multiple diseases. Understanding the underlying mechanisms of aging would help to delay and prevent age-associated diseases. Short-lived model organisms have been extensively used to study the mechanisms of aging. However, these short-lived species may be missing the longevity mechanisms that are needed to extend the lifespan of an already long-lived species such as humans. Unconventional long-lived animal species are an excellent resource to uncover novel mechanisms of longevity and disease resistance. Here, we review mechanisms that evolved in nonmodel vertebrate species to counteract age-associated diseases. Some antiaging mechanisms are conserved across species; however, various nonmodel species also evolved unique mechanisms to delay aging and prevent disease. This variety of antiaging mechanisms has evolved due to the remarkably diverse habitats and behaviors of these species. We propose that exploring a wider range of unconventional vertebrates will provide important resources to study antiaging mechanisms that are potentially applicable to humans. Expected final online publication date for the Annual Review of Genetics, Volume 55 is November 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-genet-071719-021009
Mol Cell Endocrinol. 2021 Aug 12. pii: S0303-7207(21)00266-5. [Epub ahead of print]537 111422

GDF11 protects against glucotoxicity-induced mice retinal microvascular endothelial cell dysfunction and diabetic retinopathy disease.

Wen Mei, Biao Zhu, Yi Shu, Yanhua Liang, Mei Lin, Mingjuan He, Haizhao Luo, Jingwen Ye.

  Growth differentiation factor 11 (GDF11) has been implicated in the regulation of embryonic development and age-related dysfunction, including the regulation of retinal progenitor cells. However, little is known about the functions of GDF11 in diabetic retinopathy. In this study, we demonstrated that GDF11 treatment improved diabetes-induced retinal cell death, capillary degeneration, pericyte loss, inflammation, and blood-retinal barrier breakdown in mice. Treatment of isolated mouse retinal microvascular endothelial cells with recombinant GDF11 in vitro attenuated glucotoxicity-induced retinal endothelial apoptosis and the inflammatory response. The protective mechanisms exerted are associated with TGF-β/Smad2, PI3k-Akt-FoxO1 activation，and NF-κB pathway inhibition. This study indicated that GDF11 is a novel therapeutic target for diabetic retinopathy.

Keywords:  Apoptosis; Diabetic retinopathy; GDF11; Inflammation

DOI:  https://doi.org/10.1016/j.mce.2021.111422
Front Aging Neurosci. 2021 ;13 697621

Functional Aging in Male C57BL/6J Mice Across the Life-Span: A Systematic Behavioral Analysis of Motor, Emotional, and Memory Function to Define an Aging Phenotype.

Shuichi Yanai, Shogo Endo.

  Aging is characterized generally by progressive and overall physiological decline of functions and is observed in all animals. A long line of evidence has established the laboratory mouse as the prime model of human aging. However, relatively little is known about the detailed behavioral and functional changes that occur across their lifespan, and how this maps onto the phenotype of human aging. To better understand age-related changes across the life-span, we characterized functional aging in male C57BL/6J mice of five different ages (3, 6, 12, 18, and 22 months of age) using a multi-domain behavioral test battery. Spatial memory and physical activities, including locomotor activity, gait velocity, and grip strength progressively declined with increasing age, although at different rates; anxiety-like behaviors increased with aging. Estimated age-related patterns showed that these functional alterations across ages are non-linear, and the patterns are unique for each behavioral trait. Physical function progressively declines, starting as early as 6 months of age in mice, while cognitive function begins to decline later, with considerable impairment present at 22 months of age. Importantly, functional aging of male C57BL/6J mouse starts at younger relative ages compared to when it starts in humans. Our study suggests that human-equivalent ages of mouse might be better determined on the basis of its functional capabilities.

Keywords:  aging; animal models; anxiety; behavior rating scale; handgrip strength; inbred C57BL mice; locomotion; spatial memory

DOI:  https://doi.org/10.3389/fnagi.2021.697621
eNeuro. 2021 Aug 20. pii: ENEURO.0120-21.2021. [Epub ahead of print]

Differential retinoic acid signaling in the hippocampus of aged rats with and without memory impairment.

Marta U Wołoszynowska-Fraser, Sharyn L Rossi, Jeffrey M Long, Peter J McCaffery, Peter R Rapp.

  Retinoic acid (RA), a metabolite of vitamin A, has many physiological functions, and mounting evidence points to important roles in cognition. In vitro experiments indicate that RA is involved in homeostatic synaptic scaling in the hippocampus, which supports overall network stability during learning. It has been previously determined that disrupted RA signaling in the hippocampus causes deterioration of memory, that RA signaling declines with age in brain, and that application of RA reverses this decline. Here we explore whether RA signaling is altered in an animal model of neurocognitive aging. We utilized a Morris water maze protocol to study cognitive decline in aged rats, which assesses hippocampus-dependent spatial memory and reveals substantial inter-individual differences in aged animals. Aged unimpaired (AU) rats perform on par with young, while aged impaired (AI) animals exhibit spatial memory deficits. We show that the major substrate for RA, retinol binding protein 4, is decreased in AU rats, and retinol cell surface receptor declines with chronological age. Other affected components of RA signaling include selective increases in AI animals in hippocampal synthesis (RALDH1) and catabolism of RA (CYP26B1), RA receptor α, the RA regulated ionotropic glutamate receptor (GluR1), as well as fragile X mental retardation protein. The results support the conclusion that, surprisingly, increased RA signaling in the aged hippocampus is associated with poor cognitive outcome.SIGNIFICANCE STATEMENTGrowing evidence indicates that retinoic acid (RA) function extends well beyond metabolic control and includes the regulation of memory-related synaptic plasticity. Here we explore whether RA signaling is altered in an animal model of neurocognitive aging. We show that in fact RA function is altered at nearly all levels examined, and these results are unrelated to metabolic aging. Overall, the net effect points in the direction of increased RA signaling in impaired aged animals, which may contribute to disruption in excitation/inhibition balance, a prominent feature of age-related cognitive impairment and suspected early event in the pathogenesis of Alzheimer's disease.

Keywords:  aging; hippocampus; memory; retinoic acid; spatial; vitamin A

DOI:  https://doi.org/10.1523/ENEURO.0120-21.2021
Exp Gerontol. 2021 Aug 17. pii: S0531-5565(21)00301-6. [Epub ahead of print] 111519

Prolonged caloric restriction ameliorates age-related atrophy in slow and fast muscle fibers of rat soleus muscle.

Yuhei Mizunoe, Masaki Kobayashi, Hiroki Saito, Akifumi Goto, Ryota Migitaka, Kumi Miura, Naoyuki Okita, Yuka Sudo, Ryoma Tagawa, Miki Yoshida, Ai Umemori, Yoshimi Nakagawa, Hitoshi Shimano, Yoshikazu Higami.

  Aging causes loss of skeletal muscle mass and function, which is called sarcopenia. While sarcopenia impairs the quality of life of older adults and is a major factor in long-term hospitalization, its detailed pathogenic mechanism and preventive measures remain to be identified. Caloric restriction (CR) suppresses age-related physiological and pathological changes in many species and prolongs the average and healthy life expectancy. It has recently been reported that CR suppresses the onset of sarcopenia; however, few studies have analyzed the effects of long-term CR on age-related skeletal muscle atrophy. Thus, we investigated the aging and CR effects on soleus (SOL) muscles of 9-, 24-, and 29-month-old ad libitum-fed rats (9AL, 24AL, and 29AL, respectively) and of 29-month-old CR (29CR) rats. The total muscle cross sectional area (mCSA) of the entire SOL muscle significantly decreased in the 29AL rats, but not in the 24AL rats, compared with the 9AL rats. SOL muscle of the 29AL rats exhibited marked muscle fiber atrophy and increases in the number of muscle fibers with a central nucleus, in fibrosis, and in adipocyte infiltration. Additionally, although the decrease in the single muscle fiber cross-sectional area (fCSA) and the muscle fibers' number occurred in both slow-type and fast-type muscle fibers, the degree of atrophy was more remarkable in the fast-type fibers. However, CR suppressed the muscle fiber atrophy observed in the 29AL rats' SOL muscle by preserving the mCSA and the number of muscle fibers that declined with aging, and by decreasing the number of muscle fibers with a central nucleus, fibrosis and denervated muscle fibers. Overall, these results revealed that advanced aging separately reduces the number and fCSA of each muscle fiber type, but long-term CR can ameliorate this age-related sarcopenic muscle atrophy.

Keywords:  Aging; Caloric restriction; Muscle fiber type; Skeletal muscle

DOI:  https://doi.org/10.1016/j.exger.2021.111519
Biomed Pharmacother. 2021 Aug 16. pii: S0753-3322(21)00824-6. [Epub ahead of print]142 112041

The role of mitochondria dysfunction and hepatic senescence in NAFLD development and progression.

Siarhei A Dabravolski, Evgeny E Bezsonov, Alexander N Orekhov.

  Senescence is a crucial player in several metabolic disorders and chronic inflammatory diseases. Recent data prove the involvement of hepatocyte senescence in the development of NAFLD (non-alcoholic fatty liver disease). As the main energy and ROS (reactive oxygen species) producing organelle, mitochondria play the central role in accelerated senescence and diseases development. In this review, we focus on the role of regulation of mitochondrial Ca2+ homeostasis, NAD+/NADH ratio, UPRmt (mitochondrial unfolded protein response), phospholipids and fatty acid oxidation in hepatic senescence, lifespan and NAFLD disease susceptibility. Additionally, the involvement of mitochondrial and nuclear mutations in lifespan-modulation and NAFLD development is discussed. While nuclear and mitochondria DNA mutations and SNPs (single nucleotide polymorphisms) can be used as effective diagnostic markers and targets for treatments, advanced age should be considered as an independent risk factor for NAFLD development.

Keywords:  DNA damage response; Hepatic senescence; Mitochondrial dysfunction; NAFLD; ROS; UPR(mt)

DOI:  https://doi.org/10.1016/j.biopha.2021.112041
Plant J. 2021 Aug 19.

Multiple phosphorylation events of the mitochondrial membrane protein, TTM1, regulate cell death during senescence.

Purva Karia, Keiko Yoshioka, Wolfgang Moeder.

  The role of mitochondria in programmed cell death (PCD) during animal growth and development is well documented, but much less is known for plants. We previously showed that the Arabidopsis thaliana triphosphate tunnel metalloenzyme (TTM) proteins TTM1 and TTM2 are tail-anchored proteins that localize in the mitochondrial outer membrane and participate in PCD during senescence and immunity, respectively. Here, we show that TTM1 is specifically involved in senescence induced by abscisic acid (ABA). Moreover, phosphorylation of TTM1 by multiple mitogen-activated protein kinases (MAPKs) regulates its function and turnover. A combination of proteomics and in vitro kinase assays revealed three major phosphorylation sites of TTM1 (Ser10, Ser437, and Ser490). Ser437, which is phosphorylated upon perception of senescence cues such as ABA and prolonged darkness, is phosphorylated by the MAP kinases MPK3 and MPK4, and Ser437 phosphorylation is essential for TTM1 function in senescence. These MPKs, together with three additional MAP kinases (MPK1, MPK7, and MPK6), also phosphorylate Ser10 and Ser490, marking TTM1 for protein turnover, which likely prevents uncontrolled cell death. Taken together, our results show that multiple MPKs regulate the function and turnover of the mitochondrial protein TTM1 during senescence-associated cell death, revealing a novel link between mitochondria and PCD.

Keywords:  Abscisic acid (ABA); Arabidopsis thaliana; MAP kinase; Triphosphate Tunnel Metalloenzyme (TTM); mitochondria; programmed cell death (PCD); protein phosphorylation; senescence

DOI:  https://doi.org/10.1111/tpj.15470
Int J Ophthalmol. 2021 ;14(8): 1260-1273

Therapeutic effect of Keap1-Nrf2-ARE pathway-related drugs on age-related eye diseases through anti-oxidative stress.

Zi-Yan Cai, Meng-Die Fu, Ke Liu, Xuan-Chu Duan.

  Age-related eye diseases, including cataract, glaucoma, diabetic retinopathy (DR), and age-related macular degeneration (AMD), are the leading causes of vision loss in the world. Several studies have shown that the occurrence and development of these diseases have an important relationship with oxidative stress in the eye. The Keap1-Nrf2-ARE pathway is a classical pathway that resists oxidative stress and inflammation in the body. This pathway is also active in the development of age-related eye diseases. A variety of drugs have been shown to treat age-related eye diseases through the Keap1-Nrf2-ARE (Kelch-like ECH-Associating protein 1- nuclear factor erythroid 2 related factor 2-antioxidant response element) pathway. This review describes the role of oxidative stress in the development of age-related eye diseases, the function and regulation of the Keap1-Nrf2-ARE pathway, and the therapeutic effects of drugs associated with this pathway on age-related eye diseases.

Keywords:  Keap1-Nrf2-ARE pathway; age-related eye diseases; oxidative stress

DOI:  https://doi.org/10.18240/ijo.2021.08.19
Geroscience. 2021 Aug 19.

Accumulation of C-terminal cleaved tau is distinctly associated with cognitive deficits, synaptic plasticity impairment, and neurodegeneration in aged mice.

Anjanet Loon, Frank Zamudio, Awa Sanneh, Breanna Brown, Shayna Smeltzer, Milene L Brownlow, Zainuddin Quadri, Melinda Peters, Edwin Weeber, Kevin Nash, Daniel C Lee, Marcia N Gordon, Dave Morgan, Maj-Linda B Selenica.

  C-terminal cleaved tau at D421 (∆D421-tau) accumulates in the brains of Alzheimer's disease (AD) patients. However, it is unclear how tau truncation, an understudied tau post-translational modification, contributes to AD pathology and progression. Utilizing an adeno-associated virus (AAV) gene delivery-based approach, we overexpressed full-length tau (FL-tau) and ∆D421-tau in 4- and 12-month-old mice for 4 months to study the neuropathological impact of accumulation in young adult (8-month) and middle-aged (16-month) mice. Overall, we show that independent of the tau species, age was an important factor facilitating tau phosphorylation, oligomer formation, and deposition into silver-positive tangles. However, mice overexpressing ∆D421-tau exhibited a distinct phosphorylation profile to those overexpressing FL-tau and increased tau oligomerization in the middle-age group. Importantly, overexpression of ∆D421-tau, but not FL-tau in middle-aged mice, resulted in pronounced cognitive impairments and hippocampal long-term potentiation deficits. While both FL-tau and ∆D421-tau induced neuronal loss in mice with age, ∆D421-tau led to significant neuronal loss in the CA3 area of the hippocampus and medial entorhinal cortex compared to FL-tau. Based on our data, we conclude that age increases the susceptibility to neuronal degeneration associated with ΔD421-tau accumulation. Our findings suggest that ΔD421-tau accumulation contributes to synaptic plasticity and cognitive deficits, thus representing a potential target for tau-associated pathologies.

Keywords:  Age; Cognition; Entorhinal cortex; Full-length tau; LTP; Neurodegeneration; Tauopathy; Truncated tau

DOI:  https://doi.org/10.1007/s11357-021-00408-z
Rev Assoc Med Bras (1992). 2021 Feb;pii: S0104-42302021000300173. [Epub ahead of print]67(2): 173-177

Telomere length: biological marker of cellular vitality, aging, and health-disease process.

Marcus Zulian Teixeira.

The aging process occurs due to the decline of vital physiological functions and adaptability of the body, being influenced by genetics and lifestyle. With advances in genetics, biological aging can be calculated by telomere length. Telomeres are regions at the ends of chromosomes that play a role in the maintenance and integrity of DNA. With biological aging, telomere shortening occurs, causing cellular senescence. Several studies show that shorter telomeres are associated with acute and chronic diseases, stress, addictions, and intoxications. Even in the current COVID-19 pandemic, telomere shortening is proposed as a marker of severity in individuals infected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). On the other hand, healthy lifestyle habits increase telomere length and balance of various cellular functions, preventing diseases.

DOI: https://doi.org/10.1590/1806-9282.67.02.20200655
FASEB J. 2021 Sep;35(9): e21862

Metformin and leucine increase satellite cells and collagen remodeling during disuse and recovery in aged muscle.

Jonathan J Petrocelli, Ziad S Mahmassani, Dennis K Fix, Jessie A Montgomery, Paul T Reidy, Alec I McKenzie, Naomi M de Hart, Patrick J Ferrara, Joshua J Kelley, Hiroaki Eshima, Katsuhiko Funai, Micah J Drummond.

  Loss of muscle mass and strength after disuse followed by impaired muscle recovery commonly occurs with aging. Metformin (MET) and leucine (LEU) individually have shown positive effects in skeletal muscle during atrophy conditions but have not been evaluated in combination nor tested as a remedy to enhance muscle recovery following disuse atrophy in aging. The purpose of this study was to determine if a dual treatment of metformin and leucine (MET + LEU) would prevent disuse-induced atrophy and/or promote muscle recovery in aged mice and if these muscle responses correspond to changes in satellite cells and collagen remodeling. Aged mice (22-24 months) underwent 14 days of hindlimb unloading (HU) followed by 7 or 14 days of reloading (7 or 14 days RL). MET, LEU, or MET + LEU was administered via drinking water and were compared to Vehicle (standard drinking water) and ambulatory baseline. We observed that during HU, MET + LEU resolved whole body grip strength and soleus muscle specific force decrements caused by HU. Gastrocnemius satellite cell abundance was increased with MET + LEU treatment but did not alter muscle size during disuse or recovery conditions. Moreover, MET + LEU treatment alleviated gastrocnemius collagen accumulation caused by HU and increased collagen turnover during 7 and 14 days RL driven by a decrease in collagen IV content. Transcriptional pathway analysis revealed that MET + LEU altered muscle hallmark pathways related to inflammation and myogenesis during HU. Together, the dual treatment of MET and LEU was able to increase muscle function, satellite cell content, and reduce collagen accumulation, thus improving muscle quality during disuse and recovery in aging.

Keywords:  aging; extracellular matrix; fibrosis; hindlimb unloading; inflammation; reloading

DOI:  https://doi.org/10.1096/fj.202100883R
Med Sci Sports Exerc. 2021 Sep 01. 53(9): 1873-1882

Lifelong Exercise in Age Rats Improves Skeletal Muscle Function and MicroRNA Profile.

Hao-En Gao, Fang-Hui Li, Tian Xie, Song Ma, Yi-Bo Qiao, DA-Shuai Wu, Lei Sun.

PURPOSE: Lifelong exercise is known to attenuate sarcopenia (age-associated reduction in muscle mass and function); however, the underlying molecular mechanisms remain unclear. As microRNAs are widely involved in the regulation of skeletal muscle growth and development, we aimed to evaluate the effects of lifelong regular exercise on age-related alterations in muscle microRNA expression profiles as well as on skeletal muscle atrophy, apoptosis, and mitochondria and autophagy dysfunction.
METHODS: Female 8-month-old Sprague-Dawley rats were divided into four groups; 1) 18 months of moderate-intensity continuous training (MICT) initiated at 8 months (adult-MICT, n = 12), 2) 8 months of MICT initiated at 18 months (presarcopenia-MICT, n = 12), 3) 8-month-old adult sedentary controls (adult-SED), and 4) 26-month-old aging sedentary controls (old-SED). Age skeletal muscles were then subjected to quantitative reverse transcription-polymerase chain reaction, Kyoto Encyclopedia of Genes and Genomes, immunoblotting, and miR-486 3' untranslated region luciferase reporter gene analyses.
RESULTS: Age-related loss of miR-486 expression was improved, skeletal muscle atrophy and apoptosis were downregulated, and mitochondrial activity and autophagy were upregulated in the adult-MICT group. Kyoto Encyclopedia of Genes and Genomes analysis revealed that the PI3K/Akt pathway was upregulated in adult-MICT rats compared with that in old-SED. In vitro analyses in rat skeletal muscle L6 cells further confirmed that miR-486 targets PTEN, not SAV1, thereby activating the PI3K/Akt pathway and indirectly inhibiting HIPPO signaling.
CONCLUSIONS: Compared with presarcopenia-MICT rats, adult-MICT rats experienced greater beneficial effects regarding ameliorated age-related alterations in muscle miRNA expression profile, skeletal muscle atrophy, apoptosis, and mitochondria and autophagy dysfunction, which is potentially associated with the increased miR-486 expression and concomitant targeting of the PTEN/Akt signaling pathway.

DOI: https://doi.org/10.1249/MSS.0000000000002661
iScience. 2021 Aug 20. 24(8): 102897

Lifelong dietary omega-3 fatty acid suppresses thrombotic potential through gut microbiota alteration in aged mice.

Seyed Soheil Saeedi Saravi, Nicole R Bonetti, Benoit Pugin, Florentin Constancias, Lisa Pasterk, Sara Gobbato, Alexander Akhmedov, Luca Liberale, Thomas F Lüscher, Giovanni G Camici, Jürg H Beer.

  Aging is a major risk factor for cardiovascular diseases, including thrombotic events. The gut microbiota has been implicated in the development of thrombotic risk. Plant-derived omega-3 fatty acid ɑ-linolenic acid (ALA) confers beneficial anti-platelet and anti-inflammatory effects. Hence, antithrombotic activity elicited by ALA may be partly dependent on its interaction with gut microbiota during aging. Here, we demonstrate that lifelong dietary ALA decreases platelet hyperresponsiveness and thrombus formation in aged mice. These phenotypic changes can be partly attributed to alteration of microbial composition and reduction of its metabolite trimethylamine N-oxide and inflammatory mediators including TNF-α, as well as the upregulated production of short-chain fatty acid acetate. ALA-rich diet also dampens secretion of increased procoagulant factors, tissue factor and plasminogen activator inhibitor-1, in aged mice. Our results suggest long-term ALA supplementation as an attractive, accessible, and well-tolerated nutritional strategy against age-associated platelet hyperreactivity and thrombotic potential.

Keywords:  Hematology; Microbiome; Nutrition

DOI:  https://doi.org/10.1016/j.isci.2021.102897
Mol Med Rep. 2021 Oct;pii: 719. [Epub ahead of print]24(4):

Adiponectin inhibits D‑gal‑induced cardiomyocyte senescence via AdipoR1/APPL1.

Ruiying Liu, Jing Meng, Danfei Lou.

  The aim of the present study was to examine whether adiponectin could inhibit cardiomyocyte senescence induced by D‑galactose (D‑gal), and whether it functioned via the adiponectin receptor 1 (AdipoR1)/adaptor protein phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1) signaling pathway. For this purpose, the expression levels of adiponectin, AdipoR1 and APPL1 in mouse plasma and myocardial tissues were detected via reverse transcription‑quantitative PCR (RT‑qPCR) and western blotting. An adiponectin‑overexpression plasmid was transfected into D‑gal‑treated H9c2 cells prior to the detection of AdipoR1 and APPL1 expression by RT‑qPCR. Senescence‑associated β‑galactose staining was then performed to observe cellular senescence following the transfection of small interfering RNAs (si) targeting AdipoR1 and APPL1 into D‑gal‑treated H9c2 cells overexpressing adiponectin. Commercial kits were used to detect reactive oxygen species (ROS) production and malondialdehyde (MDA) content in the different groups. The expression levels of heme oxygenase (HO)‑1 and high mobility group box 1 (HMGB1) were examined by western blot analysis. The results revealed that the expression levels of adiponectin, AdipoR1 and APPL1 were downregulated in aged mouse plasma, myocardial tissues and D‑gal‑treated cardiomyocytes. It was also observed that AdipoR1 and APPL1 expression levels were significantly upregulated following the overexpression of adiponectin into D‑gal‑treated cardiomyocytes. Moreover, adiponectin overexpression reduced cellular senescence induced by D‑gal and the expression of p16 and p21; these effects were reversed following transfection with si‑AdipoR1 and si‑APPL1. Adiponectin also downregulated the levels of ROS and MDA in D‑gal‑treated H9c2 cells via AdipoR1/APPL1. Additionally, the release of HO‑11/HMGB1 was affected by adiponectin via AdipoR1/APPL1, and adiponectin/AdipoR1/APPL1 suppressed ROS production via HO‑1/HMGB1. On the whole, the present study demonstrated that adiponectin played an inhibitory role in cardiomyocyte senescence via the AdioR1/APPL1 signaling pathway and inhibited the levels of oxidative stress in senescent cardiomyocytes via the HO‑1/HMGB1 signaling pathway.

Keywords:  adaptor protein; adiponectin; adiponectin receptor 1; cardiomyocyte senescence; phosphotyrosine interacting with PH domain and leucine zipper 1

DOI:  https://doi.org/10.3892/mmr.2021.12358
EMBO J. 2021 Aug 19. e107260

Fluc-EGFP reporter mice reveal differential alterations of neuronal proteostasis in aging and disease.

Sonja Blumenstock, Elena Katharina Schulz-Trieglaff, Kerstin Voelkl, Anna-Lena Bolender, Paul Lapios, Jana Lindner, Mark S Hipp, F Ulrich Hartl, Rüdiger Klein, Irina Dudanova.

  The cellular protein quality control machinery is important for preventing protein misfolding and aggregation. Declining protein homeostasis (proteostasis) is believed to play a crucial role in age-related neurodegenerative disorders. However, how neuronal proteostasis capacity changes in different diseases is not yet sufficiently understood, and progress in this area has been hampered by the lack of tools to monitor proteostasis in mammalian models. Here, we have developed reporter mice for in vivo analysis of neuronal proteostasis. The mice express EGFP-fused firefly luciferase (Fluc-EGFP), a conformationally unstable protein that requires chaperones for proper folding, and that reacts to proteotoxic stress by formation of intracellular Fluc-EGFP foci and by reduced luciferase activity. Using these mice, we provide evidence for proteostasis decline in the aging brain. Moreover, we find a marked reaction of the Fluc-EGFP sensor in a mouse model of tauopathy, but not in mouse models of Huntington's disease. Mechanistic investigations in primary neuronal cultures demonstrate that different types of protein aggregates have distinct effects on the cellular protein quality control. Thus, Fluc-EGFP reporter mice enable new insights into proteostasis alterations in different diseases.

Keywords:  Huntington’s disease; nuclear and cytoplasmic aggregates; protein homeostasis; reporter mouse; tauopathy

DOI:  https://doi.org/10.15252/embj.2020107260
Neurobiol Aging. 2021 Jul 25. pii: S0197-4580(21)00240-2. [Epub ahead of print]107 86-95

Emerging roles of oxidative stress in brain aging and Alzheimer's disease.

Andra Ionescu-Tucker, Carl W Cotman.

  Reactive oxygen species (ROS) are metabolic byproducts that are necessary for physiological function but can be toxic at high levels. Levels of these oxidative stressors increase gradually throughout the lifespan, impairing mitochondrial function and damaging all parts of the body, particularly the central nervous system. Emerging evidence suggests that accumulated oxidative stress may be one of the key mechanisms causing cognitive aging and neurodegenerative diseases such as Alzheimer's disease (AD). Here, we synthesize the current literature on the effect of neuronal oxidative stress on mitochondrial dysfunction, DNA damage and epigenetic changes related to cognitive aging and AD. We further describe how oxidative stress therapeutics such as antioxidants, caloric restriction and physical activity can reduce oxidation and prevent cognitive decline in brain aging and AD. Of the currently available therapeutics, we propose that long term physical activity is the most promising avenue for improving cognitive health by reducing ROS while promoting the low levels required for optimal function.

Keywords:  Alzheimer's disease; Brain aging; Cognition; Exercise; Oxidative stress

DOI:  https://doi.org/10.1016/j.neurobiolaging.2021.07.014