bims-longev Biomed News
on Longevity
Issue of 2023–05–21
fiveteen papers selected by
Andreea Nitescu
  1. SuperAger Initiative: unlocking the genetic potential of exceptional longevity.
  2. Evaluation of off-label rapamycin use to promote healthspan in 333 adults.
  3. Epigenetic Mechanisms of Aging and Aging-Associated Diseases.
  4. Potential Effects of Akkermansia Muciniphila in Aging and Aging-Related Diseases: Current Evidence and Perspectives.
  5. Inflammaging and Immunosenescence as Part of Skin Aging-A Narrative Review.
  6. Links between telomere dysfunction and hallmarks of aging.
  7. Zbp1 gene: a modulator of multiple aging hallmarks as potential therapeutic target for age-related diseases.
  8. Fecal microbiota transplantation holds the secret to youth.
  9. AI-Predicted mTOR Inhibitor Reduces Cancer Cell Proliferation and Extends the Lifespan of C. elegans.
  10. Modifiable pathways for longevity: A Mendelian randomization analysis.
  11. Rapamycin treatment increases survival, autophagy biomarkers and expression of the anti-aging klotho protein in elderly mice.
  12. Inhibiting de novo ceramide synthesis restores mitochondrial and protein homeostasis in muscle aging.
  13. The gut microbiota is an emerging target for improving brain health during ageing.
  14. Aging RNA Polymerase II may speed recklessly.
  15. Early-life telomere length predicts life-history strategy and reproductive senescence in a threatened wild songbird.
  1. Nat Aging. 2023 May 18.
    SuperAger Initiative: unlocking the genetic potential of exceptional longevity.
    Sofiya Milman, Nir Barzilai, Kara A Wilson, Odette Van der Willik, Stephanie Lederman, Thomas Perls, Tina Gao, Aoife McGovern Leahy, Praduman Jain, Aisha Montgomery, Alan R Shuldiner.
      
    DOI:  https://doi.org/10.1038/s43587-023-00429-7
  2. Geroscience. 2023 May 16.
    Evaluation of off-label rapamycin use to promote healthspan in 333 adults.
    Tammi L Kaeberlein, Alan S Green, George Haddad, Johnny Hudson, Anar Isman, Andy Nyquist, Bradley S Rosen, Yousin Suh, Sajad Zalzala, Xingyu Zhang, Mikhail V Blagosklonny, Jonathan Y An, Matt Kaeberlein.
      Rapamycin (sirolimus) is an FDA-approved drug with immune-modulating and growth-inhibitory properties. Preclinical studies have shown that rapamycin extends lifespan and healthspan metrics in yeast, invertebrates, and rodents. Several physicians are now prescribing rapamycin off-label as a preventative therapy to maintain healthspan. Thus far, however, there is limited data available on side effects or efficacy associated with use of rapamycin in this context. To begin to address this gap in knowledge, we collected data from 333 adults with a history of off-label use of rapamycin by survey. Similar data were also collected from 172 adults who had never used rapamycin. Here, we describe the general characteristics of a patient cohort using off-label rapamycin and present initial evidence that rapamycin can be used safely in adults of normal health status.
    Keywords:  Aging; COVID-19; Healthspan; Longevity; Rapamune; SARS-CoV-2; Side effects; Sirolimus
    DOI:  https://doi.org/10.1007/s11357-023-00818-1
  3. Cells. 2023 04 14. pii: 1163. [Epub ahead of print]12(8):
    Epigenetic Mechanisms of Aging and Aging-Associated Diseases.
    Annamaria la Torre, Filomena Lo Vecchio, Antonio Greco.
      Aging is an inevitable outcome of life, characterized by a progressive decline in tissue and organ function. At a molecular level, it is marked by the gradual alterations of biomolecules. Indeed, important changes are observed on the DNA, as well as at a protein level, that are influenced by both genetic and environmental parameters. These molecular changes directly contribute to the development or progression of several human pathologies, including cancer, diabetes, osteoporosis, neurodegenerative disorders and others aging-related diseases. Additionally, they increase the risk of mortality. Therefore, deciphering the hallmarks of aging represents a possibility for identifying potential druggable targets to attenuate the aging process, and then the age-related comorbidities. Given the link between aging, genetic, and epigenetic alterations, and given the reversible nature of epigenetic mechanisms, the precisely understanding of these factors may provide a potential therapeutic approach for age-related decline and disease. In this review, we center on epigenetic regulatory mechanisms and their aging-associated changes, highlighting their inferences in age-associated diseases.
    Keywords:  aging; diseases; epigenetics; histone modifications; methylation
    DOI:  https://doi.org/10.3390/cells12081163
  4. Aging Dis. 2023 Mar 28.
    Potential Effects of Akkermansia Muciniphila in Aging and Aging-Related Diseases: Current Evidence and Perspectives.
    Shi-Yu Zeng, Yi-Fu Liu, Jiang-Hua Liu, Zhao-Lin Zeng, Hui Xie, Jiang-Hua Liu.
      Akkermansia muciniphila (A. muciniphila) is an anaerobic bacterium that widely colonizes the mucus layer of the human and animal gut. The role of this symbiotic bacterium in host metabolism, inflammation, and cancer immunotherapy has been extensively investigated over the past 20 years. Recently, a growing number of studies have revealed a link between A. muciniphila, and aging and aging-related diseases (ARDs). Research in this area is gradually shifting from correlation analysis to exploration of causal relationships. Here, we systematically reviewed the association of A. muciniphila with aging and ARDs (including vascular degeneration, neurodegenerative diseases, osteoporosis, chronic kidney disease, and type 2 diabetes). Furthermore, we summarize the potential mechanisms of action of A. muciniphila and offer perspectives for future studies.
    DOI:  https://doi.org/10.14336/AD.2023.0325
  5. Int J Mol Sci. 2023 Apr 24. pii: 7784. [Epub ahead of print]24(9):
    Inflammaging and Immunosenescence as Part of Skin Aging-A Narrative Review.
    Justyna Pająk, Danuta Nowicka, Jacek C Szepietowski.
      Inflammaging and immunosenescence are associated with aging of the human body, but there are key differences between them. Immunosenescence aims to adapt the body systems to aging, while inflammaging is considered a consequence of immunosenescence. There has been much research in the area of immunosenescence and inflammaging recently, yet our understanding of aging and the ability to develop interventions to decrease the harmful effect of aging on the human body is insufficient. This review is focused on immunosenescence and inflammaging processes in the skin. We aimed to identify factors that influence inflammaging, skin aging, and their mechanisms. We discussed the role of triggering factors (e.g., UV radiations, changes in bioavailability of nitric oxide, senescence-associated secretory phenotype factors, and reactive oxygen species) and inhibiting factors that can potentially be used as anti-aging treatments, as well as the idea of geroprotectors and senotherapeutics. We concluded that while knowledge on external factors can help people to improve their health conditions, knowledge on biochemical factors can help researchers to understand inflammaging process and develop interventions to minimize the impact of aging on the human body. Further research is needed to better understand the role of factors that can slow down or accelerate inflammaging.
    Keywords:  immune system; immunity; immunosenescence; inflammaging; risk factors; skin aging
    DOI:  https://doi.org/10.3390/ijms24097784
  6. Mutat Res Genet Toxicol Environ Mutagen. 2023 May-Jun;888:pii: S1383-5718(23)00035-9. [Epub ahead of print]888 503617
    Links between telomere dysfunction and hallmarks of aging.
    Sheng Li, Zhihao Liu, Jing Zhang, Lan Li.
      Aging is characterized by the gradual loss of physiological integrity, leading to impaired function and increased risk of death. This deterioration is the main risk factor for the great majority of chronic diseases, which account for most of the morbidity, death and medical expenses. The hallmarks of aging comprise diverse molecular mechanisms and cell systems, which are interrelated and coordinated to drive the aging process. This review focuses on telomere to analyze the interrelationships between telomere dysfunction and other aging hallmarks and their relative contributions to the initiation and progression of age-related diseases (such as neurodegeneration, cardiovascular disease, and cancer), which will contribute to determine drug targets, improve human health in the aging process with minimal side effects and provide information for the prevention and treatment of age-related diseases.
    Keywords:  Aging; DNA damage response; Telomerase; Telomere dysfunction; Telomeres
    DOI:  https://doi.org/10.1016/j.mrgentox.2023.503617
  7. Biogerontology. 2023 May 18.
    Zbp1 gene: a modulator of multiple aging hallmarks as potential therapeutic target for age-related diseases.
    Mehran Radak, Hossein Fallahi.
      The Zbp1 gene has recently emerged as a potential therapeutic target for age-related diseases. Multiple studies have reported that Zbp1 plays a key role in regulating several aging hallmarks, including cellular senescence, chronic inflammation, DNA damage response, and mitochondrial dysfunction. Regarding cellular senescence, Zbp1 appears to regulate the onset and progression of senescence by controlling the expression of key markers such as p16INK4a and p21CIP1/WAF1. Similarly, evidence suggests that Zbp1 plays a role in regulating inflammation by promoting the production of pro-inflammatory cytokines, such as IL-6 and IL-1β, through activation of the NLRP3 inflammasome. Furthermore, Zbp1 seems to be involved in the DNA damage response, coordinating the cellular response to DNA damage by regulating the expression of genes such as p53 and ATM. Additionally, Zbp1 appears to regulate mitochondrial function, which is crucial for energy production and cellular homeostasis. Given the involvement of Zbp1 in multiple aging hallmarks, targeting this gene represents a potential strategy to prevent or treat age-related diseases. For example, inhibiting Zbp1 activity could be a promising approach to reduce cellular senescence and chronic inflammation, two critical hallmarks of aging associated with various age-related diseases. Similarly, modulating Zbp1 expression or activity could also improve DNA damage response and mitochondrial function, thus delaying or preventing the development of age-related diseases. Overall, the Zbp1 gene appears to be a promising therapeutic target for age-related diseases. In the current review, we have discussed the molecular mechanisms underlying the involvement of Zbp1 in aging hallmarks and proposed to develop effective strategies to target this gene for therapeutic purposes.
    Keywords:  Aging hallmarks; Cellular senescence; Chronic inflammation; DNA damage response; Mitochondrial dysfunction; Therapeutic target; Zbp1 gene
    DOI:  https://doi.org/10.1007/s10522-023-10039-w
  8. Mech Ageing Dev. 2023 May 14. pii: S0047-6374(23)00049-0. [Epub ahead of print]212 111823
    Fecal microbiota transplantation holds the secret to youth.
    Yiming Meng, Jing Sun, Guirong Zhang.
      Aging shows itself not just at the cellular level, with shortened telomeres and cell cycle arrest, but also at the organ and organismal level, with diminished brainpower, dry eyes, intestinal inflammation, muscular atrophy, wrinkles, etc. When the gut microbiota, often called the "virtual organ of the host," fails to function normally, it can lead to a cascade of health problems including, but not limited to, inflammatory bowel disease, obesity, metabolic liver disease, type II diabetes, cardiovascular disease, cancer, and even neurological disorders. An effective strategy for restoring healthy gut bacteria is fecal microbiota transplantation (FMT). It can reverse the effects of aging on the digestive system, the brain, and the vision by transplanting the functional bacteria found in the excrement of healthy individuals into the gut tracts of patients. This paves the way for future research into using the microbiome as a therapeutic target for disorders associated with aging.
    Keywords:  Aging; Ecological balance; Fecal microbiota transplantation; Gut microbiome; Recipient and donor
    DOI:  https://doi.org/10.1016/j.mad.2023.111823
  9. Int J Mol Sci. 2023 Apr 25. pii: 7850. [Epub ahead of print]24(9):
    AI-Predicted mTOR Inhibitor Reduces Cancer Cell Proliferation and Extends the Lifespan of C. elegans.
    Tinka Vidovic, Alexander Dakhovnik, Oleksii Hrabovskyi, Michael R MacArthur, Collin Y Ewald.
      The mechanistic target of rapamycin (mTOR) kinase is one of the top drug targets for promoting health and lifespan extension. Besides rapamycin, only a few other mTOR inhibitors have been developed and shown to be capable of slowing aging. We used machine learning to predict novel small molecules targeting mTOR. We selected one small molecule, TKA001, based on in silico predictions of a high on-target probability, low toxicity, favorable physicochemical properties, and preferable ADMET profile. We modeled TKA001 binding in silico by molecular docking and molecular dynamics. TKA001 potently inhibits both TOR complex 1 and 2 signaling in vitro. Furthermore, TKA001 inhibits human cancer cell proliferation in vitro and extends the lifespan of Caenorhabditis elegans, suggesting that TKA001 is able to slow aging in vivo.
    Keywords:  AI drug discovery; C. elegans; cancer; longevity; mTOR; rapalog
    DOI:  https://doi.org/10.3390/ijms24097850
  10. Clin Nutr. 2023 May 05. pii: S0261-5614(23)00140-1. [Epub ahead of print]42(6): 1041-1047
    Modifiable pathways for longevity: A Mendelian randomization analysis.
    Xiaolin Ni, Huabin Su, Yuan Lv, Rongqiao Li, Lei Liu, Yan Zhu, Ze Yang, Caiyou Hu.
       BACKGROUND: A variety of factors, including diet and lifestyle, obesity, physiology, metabolism, hormone levels, psychology, and inflammation, have been associated with longevity. The specific influences of these factors, however, are poorly understood. Here, possible causal relationships between putative modifiable risk factors and longevity are investigated.
    METHODS: A random effects model was used to investigate the association between 25 putative risk factors and longevity. The study population comprised 11,262 long-lived subjects (≥90 years old, including 3484 individuals ≥99 years old) and 25,483 controls (≤60 years old), all of European ancestry. The data were obtained from the UK Biobank database. Genetic variations were used as instruments in two-sample Mendelian randomization to reduce bias. The odds ratios for genetically predicted SD unit increases were calculated for each putative risk factor. Egger regression was used to determine possible violations of the Mendelian randomization model.
    RESULTS: Thirteen potential risk factors showed significant associations with longevity (≥90th) after correction for multiple testing. These included smoking initiation (OR:1.606; CI: 1.112-2.319) and educational attainment (OR:2.538, CI: 1.685-3.823) in the diet and lifestyle category, systolic and diastolic blood pressure (OR per SD increase: 0.518; CI: 0.438-0.614 for SBP and 0.620; CI 0.514-0.748 for DBP) and venous thromboembolism (OR:0.002; CI: 0.000-0.047) in the physiology category, obesity (OR: 0.874; CI: 0.796-0.960), BMI (OR per 1-SD increase: 0.691; CI: 0.628-0.760), and body size at age 10 (OR per 1-SD increase:0.728; CI: 0.595-0.890) in the obesity category, type 2 diabetes (T2D) (OR:0.854; CI: 0.816-0.894), LDL cholesterol (OR per 1-SD increase: 0.743; CI: 0.668-0.826), HDL cholesterol (OR per 1-SD increase: 1.243; CI: 1.112-1.390), total cholesterol (TC) (OR per 1-SD increase: 0.786; CI: 0.702-0.881), and triglycerides (TG) (OR per 1-SD increase: 0.865; CI: 0.749-0.998) in the metabolism category. Both longevity (≥90th) and super-longevity (≥99th), smoking initiation, body size at age 10, BMI, obesity, DBP, SBP, T2D, HDL, LDL, and TC were consistently associated with outcomes. The examination of underlying pathways found that BMI indirectly affected longevity through three pathways, namely, SBP, plasma lipids (HDL/TC/LDL), and T2D (p < 0.05).
    CONCLUSION: BMI was found to significantly affect longevity through SBP, plasma lipid (HDL/TC/LDL), and T2D. Future strategies should focus on modifying BMI to improve health and longevity.
    Keywords:  BMI; Longevity; Mendelian randomization; Metabolism; Risk factors
    DOI:  https://doi.org/10.1016/j.clnu.2023.04.026
  11. Pharmacol Res Perspect. 2023 Jun;11(3): e01091
    Rapamycin treatment increases survival, autophagy biomarkers and expression of the anti-aging klotho protein in elderly mice.
    Kitti Szőke, Beáta Bódi, Zoltán Hendrik, Attila Czompa, Alexandra Gyöngyösi, Donald David Haines, Zoltán Papp, Árpád Tósaki, István Lekli.
      Previous investigations have demonstrated that treatment of animals with rapamycin increases levels of autophagy, which is a process by which cells degrade intracellular detritus, thus suppressing the emergence of senescent cells, whose pro-inflammatory properties, are primary drivers of age-associated physical decline. A hypothesis is tested here that rapamycin treatment of mice approaching the end of their normal lifespan exhibits increased survival, enhanced expression of autophagic proteins; and klotho protein-a biomarker of aging that affects whole organism senescence, and systemic suppression of inflammatory mediator production. Test groups of 24-month-old C57BL mice were injected intraperitoneally with either 1.5 mg/kg/week rapamycin or vehicle. All mice administered rapamycin survived the 12-week course, whereas 43% of the controls died. Relative to controls, rapamycin-treated mice experienced minor but significant weight loss; moreover, nonsignificant trends toward decreased levels of leptin, IL-6, IL-1β, TNF-α, IL-1α, and IGF-1, along with slight elevations in VEGF, MCP-1 were observed in the blood serum of rapamycin-treated mice. Rapamycin-treated mice exhibited significantly enhanced autophagy and elevated expression of klotho protein, particularly in the kidney. Rapamycin treatment also increased cardiomyocyte Ca2+ -sensitivity and enhanced the rate constant of force re-development, which may also contribute to the enhanced survival rate in elderly mice.
    Keywords:  aging; autophagy; klotho; rapamycin; senolytics
    DOI:  https://doi.org/10.1002/prp2.1091
  12. Sci Transl Med. 2023 May 17. 15(696): eade6509
    Inhibiting de novo ceramide synthesis restores mitochondrial and protein homeostasis in muscle aging.
    Tanes I Lima, Pirkka-Pekka Laurila, Martin Wohlwend, Jean David Morel, Ludger J E Goeminne, Hao Li, Mario Romani, Xiaoxu Li, Chang-Myung Oh, Dohyun Park, Sandra Rodríguez-López, Julijana Ivanisevic, Hector Gallart-Ayala, Barbara Crisol, Florence Delort, Sabrina Batonnet-Pichon, Leonardo R Silveira, Lakshmi Sankabattula Pavani Veera Venkata, Anil K Padala, Suresh Jain, Johan Auwerx.
      Disruption of mitochondrial function and protein homeostasis plays a central role in aging. However, how these processes interact and what governs their failure in aging remain poorly understood. Here, we showed that ceramide biosynthesis controls the decline in mitochondrial and protein homeostasis during muscle aging. Analysis of transcriptome datasets derived from muscle biopsies obtained from both aged individuals and patients with a diverse range of muscle disorders revealed that changes in ceramide biosynthesis, as well as disturbances in mitochondrial and protein homeostasis pathways, are prevalent features in these conditions. By performing targeted lipidomics analyses, we found that ceramides accumulated in skeletal muscle with increasing age across Caenorhabditis elegans, mice, and humans. Inhibition of serine palmitoyltransferase (SPT), the rate-limiting enzyme of the ceramide de novo synthesis, by gene silencing or by treatment with myriocin restored proteostasis and mitochondrial function in human myoblasts, in C. elegans, and in the skeletal muscles of mice during aging. Restoration of these age-related processes improved health and life span in the nematode and muscle health and fitness in mice. Collectively, our data implicate pharmacological and genetic suppression of ceramide biosynthesis as potential therapeutic approaches to delay muscle aging and to manage related proteinopathies via mitochondrial and proteostasis remodeling.
    DOI:  https://doi.org/10.1126/scitranslmed.ade6509
  13. Gut Microbiome (Camb). 2023 ;pii: E2. [Epub ahead of print]4
    The gut microbiota is an emerging target for improving brain health during ageing.
    Marcus Boehme, Katherine Elizabeth Guzzetta, Caroline Wasén, Laura Michelle Cox.
      The gut microbiota plays crucial roles in maintaining the health and homeostasis of its host throughout lifespan, including through its ability to impact brain function and regulate behaviour during ageing. Studies have shown that there are disparate rates of biologic ageing despite equivalencies in chronologic age, including in the development of neurodegenerative diseases, which suggests that environmental factors may play an important role in determining health outcomes in ageing. Recent evidence demonstrates that the gut microbiota may be a potential novel target to ameliorate symptoms of brain ageing and promote healthy cognition. This review highlights the current knowledge around the relationships between the gut microbiota and host brain ageing, including potential contributions to age-related neurodegenerative diseases. Furthermore, we assess key areas for which gut microbiota-based strategies may present as opportunities for intervention.
    Keywords:  Gut microbiome; brain ageing; cognition; microbiota-gut-brain axis; neurodegeneration; probiotics
    DOI:  https://doi.org/10.1017/gmb.2022.11
  14. Nat Struct Mol Biol. 2023 05;30(5): 567
    Aging RNA Polymerase II may speed recklessly.
    Dimitris Typas.
      
    DOI:  https://doi.org/10.1038/s41594-023-01005-8
  15. Mol Ecol. 2023 May 12.
    Early-life telomere length predicts life-history strategy and reproductive senescence in a threatened wild songbird.
    Fay Morland, John G Ewen, Mirre J P Simons, Patricia Brekke, Nicola Hemmings.
      Telomeres are well known for their associations with lifespan and ageing across diverse taxa. Early-life telomere length can be influenced by developmental conditions and has been shown positively affect lifetime reproductive success in a limited number of studies. Whether these effects are caused by a change in lifespan, reproductive rate or perhaps most importantly reproductive senescence is unclear. Using long-term data on female breeding success from a threatened songbird (the hihi, Notiomystis cincta), we show that the early-life telomere length of individuals predicts the presence and rate of future senescence of key reproductive traits: clutch size and hatching success. In contrast, senescence of fledging success is not associated with early-life telomere length, which may be due to the added influence of biparental care at this stage. Early-life telomere length does not predict lifespan or lifetime reproductive success in this species. Females may therefore change their reproductive allocation strategy depending on their early developmental conditions, which we hypothesise are reflected in their early-life telomere length. Our results offer new insights on the role that telomeres play in reproductive senescence and individual fitness and suggest telomere length can be used as a predictor for future life history in threatened species.
    Keywords:  fitness; life history; reproduction; senescence; telomeres
    DOI:  https://doi.org/10.1111/mec.16981
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