bims-caglex Biomed News
on Cellular aging and life extension
Issue of 2023–12–03
fiveteen papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño
  1. Nucleoporin93 (Nup93) Limits Yap Activity to Prevent Endothelial Cell Senescence.
  2. Intranasal GHK peptide enhances resilience to cognitive decline in aging mice.
  3. Can Antidiabetic Medications Affect Telomere Length in Patients with Type 2 Diabetes? A Mini-Review.
  4. Mitophagy in human health, ageing and disease.
  5. U-shaped association between serum Klotho and accelerated aging among the middle-aged and elderly US population: a cross-sectional study.
  6. Understanding cellular senescence: pathways involved, therapeutics and longevity aiding.
  7. Partial cellular reprogramming: A deep dive into an emerging rejuvenation technology.
  8. Impact of NAD+ metabolism on ovarian aging.
  9. DNA damage response, a double-edged sword for vascular aging.
  10. Decoding metabolic signatures in Alzheimer's disease: a mitochondrial perspective.
  11. Therapeutic Applications of Oxysterols and Derivatives in Age-Related Diseases, Infectious and Inflammatory Diseases, and Cancers.
  12. Ergothioneine: an underrecognised dietary micronutrient required for healthy ageing?
  13. Cellular Senescence and Senolytic Agents: Recent Updates on Their Role and Applications.
  14. Endothelial cell-specific reduction in mTOR ameliorates age-related arterial and metabolic dysfunction.
  15. Natural Sirtuin1 Activators and Atherosclerosis: an Overview.
  1. bioRxiv. 2023 Nov 14. pii: 2023.11.10.566598. [Epub ahead of print]
    Nucleoporin93 (Nup93) Limits Yap Activity to Prevent Endothelial Cell Senescence.
    Tung D Nguyen, Mihir K Rao, Shaiva P Dhyani, Justin M Banks, Michael A Winek, Julka Michalkiewicz, Monica Y Lee.
      Endothelial cells (ECs) form the innermost lining of the vasculature and serve a pivotal role in preventing age-related vascular disease. Endothelial health relies on the proper nucleocytoplasmic shuttling of transcription factors via nuclear pore complexes (NPCs). Emerging studies report NPC degradation with natural aging, suggesting impaired nucleocytoplasmic transport in age-related EC dysfunction. We herein identify nucleoporin93 (Nup93), a crucial structural NPC protein, as an indispensable player for vascular protection. Endothelial Nup93 protein levels are significantly reduced in the vasculature of aged mice, paralleling observations of Nup93 loss when using in vitro models of endothelial aging. Mechanistically, we find that loss of Nup93 impairs NPC transport, leading to the nuclear accumulation of Yap and downstream inflammation. Collectively, our findings indicate maintenance of endothelial Nup93 as a key determinant of EC health, where aging targets endothelial Nup93 levels to impair NPC function as a novel mechanism for EC senescence and vascular aging.
    DOI:  https://doi.org/10.1101/2023.11.10.566598
  2. bioRxiv. 2023 Nov 17. pii: 2023.11.16.567423. [Epub ahead of print]
    Intranasal GHK peptide enhances resilience to cognitive decline in aging mice.
    Matthew Tucker, Addison Keely, Joo Young Park, Manuela Rosenfeld, Jackson Wezeman, Ruby Mangalindan, Dan Ratner, Warren Ladiges.
      Brain aging and cognitive decline are aspects of growing old. Age-related cognitive impairment entails the early stages of cognitive decline, and is extremely common, affecting millions of older people. Investigation into early cognitive decline as a treatable condition is relevant to a wide range of cognitive impairment conditions, since mild age-related neuropathology increases risk for more severe neuropathology and dementia associated with Alzheimer's Disease. Recent studies suggest that the naturally occurring peptide GHK (glycyl-L-histidyl-L-lysine) in its Cu-bound form, has the potential to treat cognitive decline associated with aging. In order to test this concept, male and female C57BL/6 mice, 20 months of age, were given intranasal GHK-Cu, 15 mg/kg daily, for two months. Results showed that mice treated with intranasal GHK-Cu had an enhanced level of cognitive performance in spatial memory and learning navigation tasks, and expressed decreased neuroinflammatory and axonal damage markers compared to mice treated with intranasal saline. These observations suggest that GHK-Cu can enhance resilience to brain aging, and has translational implications for further testing in both preclinical and clinical studies using an atomizer device for intranasal delivery.
    DOI:  https://doi.org/10.1101/2023.11.16.567423
  3. Diabetes Metab Syndr Obes. 2023 ;16 3739-3750
    Can Antidiabetic Medications Affect Telomere Length in Patients with Type 2 Diabetes? A Mini-Review.
    Baoding Qin.
      The fight against aging is an eternal pursuit of humankind. The aging rate of patients with type 2 diabetes mellitus (T2DM) is higher than that of healthy individuals. Reducing the aging rate of patients with T2DM and extending their life expectancy are challenges that endocrinologists are eager to overcome. Many studies have shown that antidiabetic medications have potent anti-aging potential. Telomeres are repetitive DNA sequences located at the ends of chromosomes, and telomere shortening is a hallmark of aging. This review summarizes clinical trials that have explored the association between antidiabetic medications and telomere length (TL) in patients with T2DM and explore the mystery of delaying aging in patients with T2DM from the perspective of telomeres. Various antidiabetic medications may have different effects on TL in patients with T2DM. Metformin and sitagliptin may protect telomeres in patients with T2DM, while exogenous insulin may promote telomere shortening in patients with T2DM. The effect of acarbose and glyburide on TL in patients with T2DM is still uncertain due to the absence of evidence from longitudinal studies.
    Keywords:  aging; antidiabetic medications; telomere length; type 2 diabetes
    DOI:  https://doi.org/10.2147/DMSO.S428560
  4. Nat Metab. 2023 Nov 30.
    Mitophagy in human health, ageing and disease.
    Anna Picca, Julie Faitg, Johan Auwerx, Luigi Ferrucci, Davide D'Amico.
      Maintaining optimal mitochondrial function is a feature of health. Mitophagy removes and recycles damaged mitochondria and regulates the biogenesis of new, fully functional ones preserving healthy mitochondrial functions and activities. Preclinical and clinical studies have shown that impaired mitophagy negatively affects cellular health and contributes to age-related chronic diseases. Strategies to boost mitophagy have been successfully tested in model organisms, and, recently, some have been translated into clinics. In this Review, we describe the basic mechanisms of mitophagy and how mitophagy can be assessed in human blood, the immune system and tissues, including muscle, brain and liver. We outline mitophagy's role in specific diseases and describe mitophagy-activating approaches successfully tested in humans, including exercise and nutritional and pharmacological interventions. We describe how mitophagy is connected to other features of ageing through general mechanisms such as inflammation and oxidative stress and forecast how strengthening research on mitophagy and mitophagy interventions may strongly support human health.
    DOI:  https://doi.org/10.1038/s42255-023-00930-8
  5. BMC Geriatr. 2023 Nov 28. 23(1): 780
    U-shaped association between serum Klotho and accelerated aging among the middle-aged and elderly US population: a cross-sectional study.
    Heng Li, Shuai Miao, Min Zhang, Peng Zhang, Yan-Bin Li, Rui-Sheng Duan.
       BACKGROUND: Phenotypic age acceleration, which reflects the difference between phenotypic age and chronological age, is an assessment to measure accelerated aging. Klotho is a protein related to slower aging, but its association with accelerated aging remains unclear.
    METHODS: Based on data from the 2007-2010 National Health and Nutrition Examination Survey, phenotypic age was calculated using chronological age and 9 aging-related biomarkers. A total of 4388 participants aged 40 to 79 years with measured serum Klotho and calculated phenotypic age were enrolled. The association between serum Klotho and phenotypic age acceleration was estimated using multivariable linear regression models. The possible nonlinear relationship was examined with smooth curve fitting. We also conducted a segmented regression model to examine the threshold effect.
    RESULTS: The association between serum Klotho and phenotypic age acceleration followed a U-shaped curve (p for nonlinearity < 0.001), with the inflection point at 870.7 pg/ml. The phenotypic age acceleration significantly decreased with the increment of serum Klotho (per SD increment: β -1.77; 95% CI, -2.57 ~ -0.98) in participants with serum Klotho < 870.7 pg/ml, and increased with the increment of serum Klotho (per SD increment:β, 1.03; 95% CI: 0.53 ~ 1.54) in participants with serum Klotho ≥ 870.7 pg/ml.
    CONCLUSION: There was a U-shaped association between serum Klotho and accelerated aging among the middle-aged and elderly US population.
    Keywords:  Accelerated aging; Klotho; NHANES; Phenotypic age; U-shaped
    DOI:  https://doi.org/10.1186/s12877-023-04479-9
  6. Cell Cycle. 2023 Nov 30. 1-22
    Understanding cellular senescence: pathways involved, therapeutics and longevity aiding.
    Ashish Kumar, Kavitha Thirumurugan.
      A normal somatic cell undergoes cycles of finite cellular divisions. The presence of surveillance checkpoints arrests cell division in response to stress inducers: oxidative stress from excess free radicals, oncogene-induced abnormalities, genotoxic stress, and telomere attrition. When facing such stress when undergoing these damages, there is a brief pause in the cell cycle to enable repair mechanisms. Also, the nature of stress determines whether the cell goes for repair or permanent arrest. As the cells experience transient or permanent stress, they subsequently choose the quiescence or senescence stage, respectively. Quiescence is an essential stage that allows the arrested/damaged cells to go through appropriate repair mechanisms and then revert to the mainstream cell cycle. However, senescent cells are irreversible and accumulate with age, resulting in inflammation and various age-related disorders. In this review, we focus on senescence-associated pathways and therapeutics understanding cellular senescence as a cascade that leads to aging, while discussing the recent details on the molecular pathways involved in regulating senescence and the benefits of therapeutic strategies against accumulated senescent cells and their secretions.
    Keywords:  DNA damage; SASP; Senescence; aging; longevity; senolytic
    DOI:  https://doi.org/10.1080/15384101.2023.2287929
  7. Aging Cell. 2023 Dec 01. e14039
    Partial cellular reprogramming: A deep dive into an emerging rejuvenation technology.
    Patrick T Paine, Ada Nguyen, Alejandro Ocampo.
      Aging and age-associated disease are a major medical and societal burden in need of effective treatments. Cellular reprogramming is a biological process capable of modulating cell fate and cellular age. Harnessing the rejuvenating benefits without altering cell identity via partial cellular reprogramming has emerged as a novel translational strategy with therapeutic potential and strong commercial interests. Here, we explore the aging-related benefits of partial cellular reprogramming while examining limitations and future directions for the field.
    Keywords:  aging; aging hallmarks; lifespan; partial cellular reprogramming; rejuvenation
    DOI:  https://doi.org/10.1111/acel.14039
  8. Immun Ageing. 2023 Dec 02. 20(1): 70
    Impact of NAD+ metabolism on ovarian aging.
    Jinghui Liang, Feiling Huang, Zhaoqi Song, Ruiyi Tang, Peng Zhang, Rong Chen.
      Nicotinamide adenine dinucleotide (NAD+), a crucial coenzyme in cellular redox reactions, is closely associated with age-related functional degeneration and metabolic diseases. NAD exerts direct and indirect influences on many crucial cellular functions, including metabolic pathways, DNA repair, chromatin remodeling, cellular senescence, and immune cell functionality. These cellular processes and functions are essential for maintaining tissue and metabolic homeostasis, as well as healthy aging. Causality has been elucidated between a decline in NAD levels and multiple age-related diseases, which has been confirmed by various strategies aimed at increasing NAD levels in the preclinical setting. Ovarian aging is recognized as a natural process characterized by a decline in follicle number and function, resulting in decreased estrogen production and menopause. In this regard, it is necessary to address the many factors involved in this complicated procedure, which could improve fertility in women of advanced maternal age. Concerning the decrease in NAD+ levels as ovarian aging progresses, promising and exciting results are presented for strategies using NAD+ precursors to promote NAD+ biosynthesis, which could substantially improve oocyte quality and alleviate ovarian aging. Hence, to acquire further insights into NAD+ metabolism and biology, this review aims to probe the factors affecting ovarian aging, the characteristics of NAD+ precursors, and the current research status of NAD+ supplementation in ovarian aging. Specifically, by gaining a comprehensive understanding of these aspects, we are optimistic about the prominent progress that will be made in both research and therapy related to ovarian aging.
    Keywords:  Infertility; Metabolic homeostasis; NAD+ metabolism; Ovary aging
    DOI:  https://doi.org/10.1186/s12979-023-00398-w
  9. Ageing Res Rev. 2023 Nov 23. pii: S1568-1637(23)00296-9. [Epub ahead of print]92 102137
    DNA damage response, a double-edged sword for vascular aging.
    Xiao Zhang, Qing Zhao, Tao Wang, Qilin Long, Yixin Sun, Liqun Jiao, Monika Gullerova.
      Vascular aging is a major risk factor for age-related cardiovascular diseases, which have high rates of morbidity and mortality. It is characterized by changes in the blood vessels, such as macroscopically increased vascular diameter and intima-medial thickness, chronic inflammation, vascular calcification, arterial stiffening, and atherosclerosis. DNA damage and the subsequent various DNA damage response (DDR) pathways are important causative factors of vascular aging. Deficient DDR, which may result in the accumulation of unrepaired damaged DNA or mutations, can lead to vascular aging. On the other hand, over-activation of some DDR proteins, such as poly (ADP ribose) polymerase (PARP) and ataxia telangiectasia mutated (ATM), also can enhance the process of vascular aging, suggesting that DDR can have both positive and negative effects on vascular aging. Despite the evidence reviewed in this paper, the role of DDR in vascular aging and potential therapeutic targets remain poorly understood and require further investigation.
    Keywords:  DNA damage response; Deficiency; Overactivation; Potential therapy; Vascular aging
    DOI:  https://doi.org/10.1016/j.arr.2023.102137
  10. Cell Death Discov. 2023 Dec 01. 9(1): 432
    Decoding metabolic signatures in Alzheimer's disease: a mitochondrial perspective.
    Daniele Bano, Dan Ehninger, Giacinto Bagetta.
      Alzheimer's disease (AD) is one of the most prevalent age-related neurodegenerative diseases and accounts for the majority of dementia cases worldwide. Tremendous ongoing efforts of basic and clinical research have expanded our knowledge on AD and its complex multifactorial pathogenesis. For sporadic AD, it is widely assumed that silent and early symptomatic stages initiate decades before the irreversible decline in cognitive abilities that ultimately lead to debilitating conditions. In addition to amyloid plaques and tau-containing neurofibrillary tangles as the most prominent hallmarks of AD lesions within the affected brain areas, we now possess a broader collection of pathological signatures that are associated with AD development and progression. In this regard, there is a substantial body of evidence suggesting that hypometabolism occurs in the brains of individuals at the prodromal stage before dementia is diagnosed, which may reflect an early role of metabolic dysfunction in AD. This perspective surveys the vast literature and critically assesses the current evidence demonstrating a mitochondrial contribution to AD. Additionally, we discuss our interpretations of the reported mitochondrial signatures and consider how altered mitochondrial bioenergetics may be an additional risk factor for AD pathogenesis.
    DOI:  https://doi.org/10.1038/s41420-023-01732-3
  11. Adv Exp Med Biol. 2024 ;1440 379-400
    Therapeutic Applications of Oxysterols and Derivatives in Age-Related Diseases, Infectious and Inflammatory Diseases, and Cancers.
    Mohamed Ksila, Imen Ghzaiel, Khouloud Sassi, Amira Zarrouk, Valerio Leoni, Giuseppe Poli, Leila Rezig, Vivien Pires, Smail Meziane, Atanas G Atanasov, Sonia Hammami, Mohamed Hammami, Olfa Masmoudi-Kouki, Oumaima Hamdi, Pierre Jouanny, Mohammad Samadi, Anne Vejux, Taoufik Ghrairi, Gérard Lizard.
      Oxysterols, resulting from the oxidation of cholesterol, are formed either by autoxidation, enzymatically, or by both processes. These molecules, which are provided in more or less important quantities depending on the type of diet, are also formed in the body and their presence is associated with a normal physiological activity. Their increase and decrease at the cellular level and in biological fluids can have significant consequences on health due or not to the interaction of some of these molecules with different types of receptors but also because oxysterols are involved in the regulation of RedOx balance, cytokinic and non-cytokinic inflammation, lipid metabolism, and induction of cell death. Currently, various pathologies such as age-related diseases, inflammatory and infectious diseases, and several cancers are associated with abnormal levels of oxysterols. Due to the important biological activities of oxysterols, their interaction with several receptors and their very likely implications in several diseases, this review focuses on these molecules and on oxysterol derivatives, which are often more efficient, in a therapeutic context. Currently, several oxysterol derivatives are developed and are attracting a lot of interest.
    Keywords:  Age-related diseases; Alzheimer’s disease; Cancer; Cardiovascular diseases; Eye diseases; Infectious diseases; Inflammatory diseases; Osteoporosis; Oxysterols; Therapeutic applications
    DOI:  https://doi.org/10.1007/978-3-031-43883-7_19
  12. Br J Nutr. 2023 Jan 14. 129(1): 104-114
    Ergothioneine: an underrecognised dietary micronutrient required for healthy ageing?
    Xiaoying Tian, James L Thorne, J Bernadette Moore.
      Ergothioneine is a naturally occurring amino acid and thiol antioxidant found in high amounts in mushrooms and fermented foods. Humans and animals acquire ergothioneine from the diet through the pH-dependent activity of a membrane transporter, the large solute carrier 22A member 4 (SLC22A4), expressed on the apical membrane of the small intestine. The SLC22A4 transporter also functions in the renal reabsorption of ergothioneine in the kidney, with avid absorption and retention of ergothioneine from the diet observed in both animals and humans. Ergothioneine is capable of scavenging a diverse range of reactive oxygen and nitrogen species, has metal chelation properties, and is predicted to directly regulate nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Although not lethal, the genetic knockout of the SLC22A4 gene in multiple organisms increases susceptibility to oxidative stress, damage and inflammation; in agreement with a large body of preclinical data suggesting the physiological function of ergothioneine is as a cellular antioxidant and cytoprotectant agent. In humans, blood levels of ergothioneine decline after the age of 60 years, and lower levels of ergothioneine are associated with more rapid cognitive decline. Conversely, high plasma ergothioneine levels have been associated with significantly reduced cardiovascular mortality and overall mortality risks. In this horizon’s manuscript, we review evidence suggesting critical roles for dietary ergothioneine in healthy ageing and the prevention of cardiometabolic disease. We comment on some of the outstanding research questions in the field and consider the question of whether or not ergothioneine should be considered a conditionally essential micronutrient.
    Keywords:  CVD; Cardiometabolic disease; Ergothioneine; Non-alcoholic fatty liver disease; Type 2 diabetes
    DOI:  https://doi.org/10.1017/S0007114522003592
  13. Curr Top Med Chem. 2023 Nov 30.
    Cellular Senescence and Senolytic Agents: Recent Updates on Their Role and Applications.
    Lokesh Chandrakar, Gopal Khatik, Ramesh Ambatwar.
      Cellular senescence, an eternal condition of cell cycle arrest due to cellular stressors, is a sign of aging. Senescent cells (SCs) build up in tissues as they age, impairing their ability to repair themselves by causing the cell cycle to seize in progenitor cells and producing proinflammatory and the senescence-associated secretory phenotype (SASP) or matrix-degrading molecules. SASP aids in the emergence of several age-related diseases. Genetic studies have shown that removing SCs can delay aging and prolong life. Senolytics are small molecules designed to treat numerous age-related disorders can selectively kill SCs. A detailed discussion on senolytics and their potential as therapeutics to treat neuro-disorder and slow down aging is described herein. Emerging natural products, such as quercetin, dasatinib, fisetin, piperlongumine, and curcumin, have recently been reported to be effective senolytic agents, and some structurally modified analogue of these have also been explored for better selectivity and efficacy in animal models. These showed significant potential in clinical studies and could be developed as senolytic drugs in the future.
    Keywords:  Cellular senescence; ageing; natural products.; senolytic agents; senolytic targets
    DOI:  https://doi.org/10.2174/0115680266273698231107110956
  14. Aging Cell. 2023 Nov 28. e14040
    Endothelial cell-specific reduction in mTOR ameliorates age-related arterial and metabolic dysfunction.
    Md Torikul Islam, Shelby A Hall, Tavia Dutson, Samuel I Bloom, R Colton Bramwell, John Kim, Jordan R Tucker, Daniel R Machin, Anthony J Donato, Lisa A Lesniewski.
      Systemic inhibition of the mammalian target of rapamycin (mTOR) delays aging and many age-related conditions including arterial and metabolic dysfunction. However, the mechanisms and tissues involved in these beneficial effects remain largely unknown. Here, we demonstrate that activation of S6K, a downstream target of mTOR, is increased in arteries with advancing age, and that this occurs preferentially in the endothelium compared with the vascular smooth muscle. Induced endothelial cell-specific deletion of mTOR reduced protein expression by 60-70%. Although this did not significantly alter arterial and metabolic function in young mice, endothelial mTOR reduction reversed arterial stiffening and improved endothelium-dependent dilation (EDD) in old mice, indicating an improvement in age-related arterial dysfunction. Improvement in arterial function in old mice was concomitant with reductions in arterial cellular senescence, inflammation, and oxidative stress. The reduction in endothelial mTOR also improved glucose tolerance in old mice, and this was associated with attenuated hepatic gluconeogenesis and improved lipid tolerance, but was independent of alterations in peripheral insulin sensitivity, pancreatic beta cell function, or fasted plasma lipids in old mice. Lastly, we found that endothelial mTOR reduction suppressed gene expression of senescence and inflammatory markers in endothelial-rich (i.e., lung) and metabolically active organs (i.e., liver and adipose tissue), which may have contributed to the improvement in metabolic function in old mice. This is the first evidence demonstrating that reducing endothelial mTOR in old age improves arterial and metabolic function. These findings have implications for future drug development.
    Keywords:  aging; arterial stiffness; endothelial cells; inflammation; metabolic function; oxidative stress; senescence; vasodilation
    DOI:  https://doi.org/10.1111/acel.14040
  15. Curr Atheroscler Rep. 2023 Dec 01.
    Natural Sirtuin1 Activators and Atherosclerosis: an Overview.
    Karolina Łanoszka, Nimasha Vlčková.
       PURPOSE OF REVIEW: The purpose of this review is to summarize the most recent findings investigating the impact of several natural sirtuin (SIRT) activators, particularly SIRT1, on atherosclerosis.
    RECENT FINDINGS: Sirtuins that belong to a family of class III histone deacetylases are believed to be novel therapeutic targets to treat age-related and chronic diseases. SIRT expression is regulated by small molecules called SIRT-activating compounds that can be found in natural food products. SIRT1 may exert protective effects in atherosclerosis, which is said to be a major cause of cardiovascular diseases. Most of the evidence supporting the beneficial effects of these natural compounds comes from in vitro or animal-based studies, while there have been particularly few or inconsistent human-based studies evaluating their long-term impact in recent years. SIRT1 activation has been demonstrated to mitigate or prevent atherosclerosis through various mechanisms. However, further research is required to determine the optimal SIRT activator dosage and to establish a stronger correlation between health effects and the administration of bioactive compounds. Additionally, conducting more human clinical trials is necessary to ensure the safety of these compounds for preventing atherosclerosis development.
    Keywords:  Atherosclerosis; Natural compounds; SIRT1; SIRT1 activators
    DOI:  https://doi.org/10.1007/s11883-023-01165-4
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