bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2023–04–30
fifty-four papers selected by
Ayesh Seneviratne, Western University
  1. Epigenetic reversal of hematopoietic stem cell aging in Phf6-knockout mice.
  2. Germline dysfunction accelerates organismal aging.
  3. Flawed translation leads to premature aging.
  4. A state-of-the-art review on the MicroRNAs roles in hematopoietic stem cell aging and longevity.
  5. Endogenous retroviruses and aging.
  6. Recent advances in understanding the impact of infection and inflammation on hematopoietic stem and progenitor cells.
  7. Loss of epigenetic information drives aging.
  8. Spurious intragenic transcription is a feature of mammalian cellular senescence and tissue aging.
  9. Why Gilgamesh failed: the mechanistic basis of the limits to human lifespan.
  10. Pleiotropic effects of mitochondria in aging.
  11. Principal component analysis improves reliability of epigenetic aging biomarkers.
  12. Editorial: Nutrition and metabolic aging.
  13. The degree of frailty as a translational measure of health in aging.
  14. Exercise protects vascular function by countering senescent cells in older adults.
  15. Telomere dysfunction in chronic liver disease: The link from aging.
  16. An inflammatory clock for healthy aging.
  17. Missing checkpoints in premature aging.
  18. Aging and frailty immune landscape.
  19. The economic value of targeting aging.
  20. Recent clinical trials with stem cells to slow or reverse normal aging processes.
  21. How systems biology can help solve the enigma of aging.
  22. Author Correction: An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging.
  23. The importance of aging in cancer research.
  24. Cerebrospinal fluid immune environment during aging.
  25. Engineering longevity-design of a synthetic gene oscillator to slow cellular aging.
  26. Niche stiffness regulates stem cell aging.
  27. Chromatin remodeling due to degradation of citrate carrier impairs osteogenesis of aged mesenchymal stem cells.
  28. Decreased spliceosome fidelity and egl-8 intron retention inhibit mTORC1 signaling to promote longevity.
  29. T cells proliferate beyond organismal lifespan.
  30. Healthspan extension in aged mice by cyclic induction of a FOXM1 transgene.
  31. Mendelian randomization of genetically independent aging phenotypes identifies LPA and VCAM1 as biological targets for human aging.
  32. CISH impairs lysosomal function in activated T cells resulting in mitochondrial DNA release and inflammaging.
  33. Human lifespan is linked to truncating variants in single genes.
  34. Machine learning to spot frailty in aging mice.
  35. Achieving a three-dimensional longevity dividend.
  36. Harnessing light energy to charge mitochondria and extend lifespan.
  37. Aging Like Struldbruggs, Dorian Gray or Peter Pan.
  38. Cryptic initiation drives transcriptional junk in ageing.
  39. Healthy aging and muscle function are positively associated with NAD+ abundance in humans.
  40. Nutritional Programming of the Lifespan of Male Drosophila by Activating FOXO on Larval Low-Nutrient Diet.
  41. The energy-splicing resilience axis hypothesis of aging.
  42. piRNAs regulate a Hedgehog germline-to-soma pro-aging signal.
  43. Rare genetic coding variants associated with human longevity and protection against age-related diseases.
  44. Senescent cells, senolytics and tissue repair: the devil may be in the dosing.
  45. How does the body know how old it is?
  46. A senolytic strategy integrating multiple technologies delays aging.
  47. NAD+ boosting brings tears to aging eyes.
  48. Skin chronological aging drives age-related bone loss via secretion of cystatin-A.
  49. The Warburg effect: a signature of mitochondrial overload.
  50. Cell-type-specific aging clocks to quantify aging and rejuvenation in neurogenic regions of the brain.
  51. Changes in neurovascular function in brain microvessels during aging.
  52. Enhanced brain mitophagy slows systemic aging.
  53. Aging breaks liver vascular 'zone defense'.
  54. Young microbiota rejuvenates the aging brain.
  1. Nat Aging. 2022 Nov;2(11): 1008-1023
    Epigenetic reversal of hematopoietic stem cell aging in Phf6-knockout mice.
    Agnieszka A Wendorff, S Aidan Quinn, Silvia Alvarez, Jessie A Brown, Mayukh Biswas, Thomas Gunning, Teresa Palomero, Adolfo A Ferrando.
      Aging is characterized by an accumulation of myeloid-biased hematopoietic stem cells (HSCs) with reduced developmental potential. Genotoxic stress and epigenetic alterations have been proposed to mediate age-related HSC loss of regenerative and self-renewal potential. However, the mechanisms underlying these changes remain largely unknown. Genetic inactivation of the plant homeodomain 6 (Phf6) gene, a nucleolar and chromatin-associated factor, antagonizes age-associated HSC decline. Immunophenotyping, single-cell transcriptomic analyses and transplantation assays demonstrated markedly decreased accumulation of immunophenotypically defined HSCs, reduced myeloid bias and increased hematopoietic reconstitution capacity with preservation of lymphoid differentiation potential in Phf6-knockout HSCs from old mice. Moreover, deletion of Phf6 in aged mice rejuvenated immunophenotypic, transcriptional and functional hallmarks of aged HSCs. Long-term HSCs from old Phf6-knockout mice showed epigenetic rewiring and transcriptional programs consistent with decreased genotoxic stress-induced HSC aging. These results identify Phf6 as an important epigenetic regulator of HSC aging.
    DOI:  https://doi.org/10.1038/s43587-022-00304-x
  2. Nat Aging. 2022 Nov;2(11): 977
    Germline dysfunction accelerates organismal aging.
    Sebastien Thuault.
      
    DOI:  https://doi.org/10.1038/s43587-022-00314-9
  3. Nat Aging. 2022 Apr;2(4): 276
    Flawed translation leads to premature aging.
    Manlio Vinciguerra.
      
    DOI:  https://doi.org/10.1038/s43587-022-00215-x
  4. Cell Commun Signal. 2023 04 24. 21(1): 85
    A state-of-the-art review on the MicroRNAs roles in hematopoietic stem cell aging and longevity.
    Geovanny Genaro Reivan Ortiz, Yasaman Mohammadi, Ahmad Nazari, Mehrnaz Ataeinaeini, Parisa Kazemi, Saman Yasamineh, Bashar Zuhair Talib Al-Naqeeb, Haider Kamil Zaidan, Omid Gholizadeh.
      Aging is a biological process determined through time-related cellular and functional impairments, leading to a decreased standard of living for the organism. Recently, there has been an unprecedented advance in the aging investigation, especially the detection that the rate of senescence is at least somewhat regulated via evolutionarily preserved genetic pathways and biological processes. Hematopoietic stem cells (HSCs) maintain blood generation over the whole lifetime of an organism. The senescence process influences many of the natural features of HSC, leading to a decline in their capabilities, independently of their microenvironment. New studies show that HSCs are sensitive to age-dependent stress and gradually lose their self-renewal and regeneration potential with senescence. MicroRNAs (miRNAs) are short, non-coding RNAs that post-transcriptionally inhibit translation or stimulate target mRNA cleavage of target transcripts via the sequence-particular connection. MiRNAs control various biological pathways and processes, such as senescence. Several miRNAs are differentially expressed in senescence, producing concern about their use as moderators of the senescence process. MiRNAs play an important role in the control of HSCs and can also modulate processes associated with tissue senescence in specific cell types. In this review, we display the contribution of age-dependent alterations, including DNA damage, epigenetic landscape, metabolism, and extrinsic factors, which affect HSCs function during aging. In addition, we investigate the particular miRNAs regulating HSCs senescence and age-associated diseases. Video Abstract.
    Keywords:  Aging; Anti-aging; Hematopoietic stem cell; MicroRNA
    DOI:  https://doi.org/10.1186/s12964-023-01117-0
  5. Nat Aging. 2023 Feb;3(2): 145
    Endogenous retroviruses and aging.
    Sebastien Thuault.
      
    DOI:  https://doi.org/10.1038/s43587-023-00377-2
  6. Cells Dev. 2023 Apr 24. pii: S2667-2901(23)00020-7. [Epub ahead of print] 203844
    Recent advances in understanding the impact of infection and inflammation on hematopoietic stem and progenitor cells.
    Michael D Milsom, Marieke A G Essers.
      Just over one decade ago, it was discovered that hematopoietic stem cells (HSCs) could directly respond to inflammatory cytokines by mounting a proliferative response thought to mediate the emergency production of mature blood cells. In the intervening years, we have gained mechanistic insight into this so-called activation process and have started to learn such a response may come at a cost in terms of ultimately resulting in HSC exhaustion and hematologic dysfunction. In this review article, we report the progress we have made in understanding the interplay between infection, inflammation and HSCs during the funding period of the Collaborative Research Center 873 "Maintenance and Differentiation of Stem Cells in Development and Disease", and place this work within the context of recent output by others working within this field.
    Keywords:  Aging; Clonal hematopoiesis; Hematopoietic stem cells; Infection; Inflammation
    DOI:  https://doi.org/10.1016/j.cdev.2023.203844
  7. Nat Aging. 2023 Feb;3(2): 142
    Loss of epigenetic information drives aging.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-023-00372-7
  8. Nat Aging. 2023 Apr;3(4): 402-417
    Spurious intragenic transcription is a feature of mammalian cellular senescence and tissue aging.
    Payel Sen, Greg Donahue, Catherine Li, Gabor Egervari, Na Yang, Yemin Lan, Neil Robertson, Parisha P Shah, Erik Kerkhoven, David C Schultz, Peter D Adams, Shelley L Berger.
      Mammalian aging is characterized by the progressive loss of tissue function and increased risk for disease. Accumulation of senescent cells in aging tissues partly contributes to this decline, and targeted depletion of senescent cells in vivo ameliorates many age-related phenotypes. The fundamental molecular mechanisms responsible for the decline of cellular health and fitness during senescence and aging are largely unknown. In this study, we investigated whether chromatin-mediated loss of transcriptional fidelity, known to contribute to fitness and survival in yeast and worms, also occurs during human cellular senescence and mouse aging. Our findings reveal aberrant transcription initiation inside genes during senescence and aging that co-occurs with changes in the chromatin landscape. Interventions that alter these spurious transcripts have profound consequences on cellular health, primarily affecting intracellular signal transduction pathways. We propose that age-related spurious transcription promotes a noisy transcriptome and degradation of coherent transcriptional networks.
    DOI:  https://doi.org/10.1038/s43587-023-00384-3
  9. Nat Aging. 2022 Oct;2(10): 878-884
    Why Gilgamesh failed: the mechanistic basis of the limits to human lifespan.
    Brandon Milholland, Jan Vijg.
      The purpose of this Perspective is to clarify for an interdisciplinary audience the fundamental concepts of human longevity and provide evidence for a limit to human lifespan. This observed limit is placed into a broader framework by showing how it has arisen through the process of evolution and by enumerating the molecular mechanisms that may enforce it. Finally, we look toward potential future developments and the prospects for possibly circumventing the current limit.
    DOI:  https://doi.org/10.1038/s43587-022-00291-z
  10. Nat Aging. 2022 Mar;2(3): 199-213
    Pleiotropic effects of mitochondria in aging.
    Tanes Lima, Terytty Yang Li, Adrienne Mottis, Johan Auwerx.
      Aging is typified by a progressive decline in mitochondrial activity and stress resilience. Here, we review how mitochondrial stress pathways have pleiotropic effects on cellular and systemic homeostasis, which can comprise protective or detrimental responses during aging. We describe recent evidence arguing that defects in these conserved adaptive pathways contribute to aging and age-related diseases. Signaling pathways regulating the mitochondrial unfolded protein response, mitochondrial membrane dynamics, and mitophagy are discussed, emphasizing how their failure contributes to heteroplasmy and de-regulation of key metabolites. Our current understanding of how these processes are controlled and interconnected explains how mitochondria can widely impact fundamental aspects of aging.
    DOI:  https://doi.org/10.1038/s43587-022-00191-2
  11. Nat Aging. 2022 Jul;2(7): 578-579
    Principal component analysis improves reliability of epigenetic aging biomarkers.
      
    DOI:  https://doi.org/10.1038/s43587-022-00253-5
  12. Front Nutr. 2023 ;10 1191958
    Editorial: Nutrition and metabolic aging.
    Devin Wahl, Zachary S Clayton.
      
    Keywords:  aging; calorie restriction; health span; metabolic health; nutrition
    DOI:  https://doi.org/10.3389/fnut.2023.1191958
  13. Nat Aging. 2021 Aug;1(8): 651-665
    The degree of frailty as a translational measure of health in aging.
    Susan E Howlett, Andrew D Rutenberg, Kenneth Rockwood.
      Frailty is a multiply determined, age-related state of increased risk for adverse health outcomes. We review how the degree of frailty conditions the development of late-life diseases and modifies their expression. The risks for frailty range from subcellular damage to social determinants. These risks are often synergistic-circumstances that favor damage also make repair less likely. We explore how age-related damage and decline in repair result in cellular and molecular deficits that scale up to tissue, organ and system levels, where they are jointly expressed as frailty. The degree of frailty can help to explain the distinction between carrying damage and expressing its usual clinical manifestations. Studying people-and animals-who live with frailty, including them in clinical trials and measuring the impact of the degree of frailty are ways to better understand the diseases of old age and to establish best practices for the care of older adults.
    DOI:  https://doi.org/10.1038/s43587-021-00099-3
  14. Front Physiol. 2023 ;14 1138162
    Exercise protects vascular function by countering senescent cells in older adults.
    Jinqi Meng, Qi Geng, Sheng Jin, Xu Teng, Lin Xiao, Yuming Wu, Danyang Tian.
      Blood vessels are key conduits for the transport of blood and circulating factors. Abnormalities in blood vessels promote cardiovascular disease (CVD), which has become the most common disease as human lifespans extend. Aging itself is not pathogenic; however, the decline of physiological and biological function owing to aging has been linked to CVD. Although aging is a complex phenomenon that has not been comprehensively investigated, there is accumulating evidence that cellular senescence aggravates various pathological changes associated with aging. Emerging evidence shows that approaches that suppress or eliminate cellular senescence preserve vascular function in aging-related CVD. However, most pharmacological therapies for treating age-related CVD are inefficient. Therefore, effective approaches to treat CVD are urgently required. The benefits of exercise for the cardiovascular system have been well documented in basic research and clinical studies; however, the mechanisms and optimal frequency of exercise for promoting cardiovascular health remain unknown. Accordingly, in this review, we have discussed the changes in senescent endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) that occur in the progress of CVD and the roles of physical activity in CVD prevention and treatment.
    Keywords:  aging; cardiovascular diseases; exercise; senescence; vascular function
    DOI:  https://doi.org/10.3389/fphys.2023.1138162
  15. Hepatology. 2023 Apr 28.
    Telomere dysfunction in chronic liver disease: The link from aging.
    Daniel D Penrice, Nidhi Jalan-Sakrikar, Diana Jurk, João F Passos, Douglas A Simonetto.
      
    DOI:  https://doi.org/10.1097/HEP.0000000000000426
  16. Nat Aging. 2021 Jul;1(7): 574-575
    An inflammatory clock for healthy aging.
    M Luisa Iruela-Arispe.
      
    DOI:  https://doi.org/10.1038/s43587-021-00085-9
  17. Nat Aging. 2023 Feb;3(2): 146-147
    Missing checkpoints in premature aging.
    Huijing Xue, Kan Cao.
      
    DOI:  https://doi.org/10.1038/s43587-022-00351-4
  18. Nat Aging. 2022 Apr;2(4): 280-281
    Aging and frailty immune landscape.
    Roel P H De Maeyer, Arne N Akbar.
      
    DOI:  https://doi.org/10.1038/s43587-022-00208-w
  19. Nat Aging. 2021 Jul;1(7): 616-623
    The economic value of targeting aging.
    Andrew J Scott, Martin Ellison, David A Sinclair.
      Developments in life expectancy and the growing emphasis on biological and 'healthy' aging raise a number of important questions for health scientists and economists alike. Is it preferable to make lives healthier by compressing morbidity, or longer by extending life? What are the gains from targeting aging itself compared to efforts to eradicate specific diseases? Here we analyze existing data to evaluate the economic value of increases in life expectancy, improvements in health and treatments that target aging. We show that a compression of morbidity that improves health is more valuable than further increases in life expectancy, and that targeting aging offers potentially larger economic gains than eradicating individual diseases. We show that a slowdown in aging that increases life expectancy by 1 year is worth US$38 trillion, and by 10 years, US$367 trillion. Ultimately, the more progress that is made in improving how we age, the greater the value of further improvements.
    DOI:  https://doi.org/10.1038/s43587-021-00080-0
  20. Front Aging. 2023 ;4 1148926
    Recent clinical trials with stem cells to slow or reverse normal aging processes.
    Ricardo P Garay.
      Aging is associated with a decline in the regenerative potential of stem cells. In recent years, several clinical trials have been launched in order to evaluate the efficacy of mesenchymal stem cell interventions to slow or reverse normal aging processes (aging conditions). Information concerning those clinical trials was extracted from national and international databases (United States, EU, China, Japan, and World Health Organization). Mesenchymal stem cell preparations were in development for two main aging conditions: physical frailty and facial skin aging. With regard to physical frailty, positive results have been obtained in phase II studies with intravenous Lomecel-B (an allogeneic bone marrow stem cell preparation), and a phase I/II study with an allogeneic preparation of umbilical cord-derived stem cells was recently completed. With regard to facial skin aging, positive results have been obtained with an autologous preparation of adipose-derived stem cells. A further sixteen clinical trials for physical frailty and facial skin aging are currently underway. Reducing physical frailty with intravenous mesenchymal stem cell administration can increase healthy life expectancy and decrease costs to the public health system. However, intravenous administration runs the risk of entrapment of the stem cells in the lungs (and could raise safety concerns). In addition to aesthetic purposes, clinical research on facial skin aging allows direct evaluation of tissue regeneration using sophisticated and precise methods. Therefore, research on both conditions is complementary, which facilitates a global vision.
    Keywords:  aging; clinical trial; frailty; lomecel-B; mesenchymal stem cells; rejuvenation; skin aging; stem cells
    DOI:  https://doi.org/10.3389/fragi.2023.1148926
  21. Nat Aging. 2021 Sep;1(9): 750-752
    How systems biology can help solve the enigma of aging.
    Marie Anne O'Donnell, Briony Jain.
      
    DOI:  https://doi.org/10.1038/s43587-021-00115-6
  22. Nat Aging. 2021 Aug;1(8): 748
    Author Correction: An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging.
    Nazish Sayed, Yingxiang Huang, Khiem Nguyen, Zuzana Krejciova-Rajaniemi, Anissa P Grawe, Tianxiang Gao, Robert Tibshirani, Trevor Hastie, Ayelet Alpert, Lu Cui, Tatiana Kuznetsova, Yael Rosenberg-Hasson, Rita Ostan, Daniela Monti, Benoit Lehallier, Shai S Shen-Orr, Holden T Maecker, Cornelia L Dekker, Tony Wyss-Coray, Claudio Franceschi, Vladimir Jojic, François Haddad, José G Montoya, Joseph C Wu, Mark M Davis, David Furman.
      
    DOI:  https://doi.org/10.1038/s43587-021-00102-x
  23. Nat Aging. 2022 May;2(5): 365-366
    The importance of aging in cancer research.
      
    DOI:  https://doi.org/10.1038/s43587-022-00231-x
  24. Nat Aging. 2023 Jan;3(1): 4
    Cerebrospinal fluid immune environment during aging.
    Ashley Castellanos-Jankiewicz.
      
    DOI:  https://doi.org/10.1038/s43587-022-00356-z
  25. Science. 2023 Apr 28. 380(6643): 376-381
    Engineering longevity-design of a synthetic gene oscillator to slow cellular aging.
    Zhen Zhou, Yuting Liu, Yushen Feng, Stephen Klepin, Lev S Tsimring, Lorraine Pillus, Jeff Hasty, Nan Hao.
      Synthetic biology enables the design of gene networks to confer specific biological functions, yet it remains a challenge to rationally engineer a biological trait as complex as longevity. A naturally occurring toggle switch underlies fate decisions toward either nucleolar or mitochondrial decline during the aging of yeast cells. We rewired this endogenous toggle to engineer an autonomous genetic clock that generates sustained oscillations between the nucleolar and mitochondrial aging processes in individual cells. These oscillations increased cellular life span through the delay of the commitment to aging that resulted from either the loss of chromatin silencing or the depletion of heme. Our results establish a connection between gene network architecture and cellular longevity that could lead to rationally designed gene circuits that slow aging.
    DOI:  https://doi.org/10.1126/science.add7631
  26. Nat Aging. 2022 Jul;2(7): 568-569
    Niche stiffness regulates stem cell aging.
    Chae Ho Lim, Mayumi Ito.
      
    DOI:  https://doi.org/10.1038/s43587-022-00259-z
  27. Nat Aging. 2021 Sep;1(9): 810-825
    Chromatin remodeling due to degradation of citrate carrier impairs osteogenesis of aged mesenchymal stem cells.
    Andromachi Pouikli, Swati Parekh, Monika Maleszewska, Chrysa Nikopoulou, Maarouf Baghdadi, Ignacio Tripodi, Kat Folz-Donahue, Yvonne Hinze, Andrea Mesaros, David Hoey, Patrick Giavalisco, Robin Dowell, Linda Partridge, Peter Tessarz.
      Aging is accompanied by a general decline in the function of many cellular pathways. However, whether these are causally or functionally interconnected remains elusive. Here, we study the effect of mitochondrial-nuclear communication on stem cell aging. We show that aged mesenchymal stem cells exhibit reduced chromatin accessibility and lower histone acetylation, particularly on promoters and enhancers of osteogenic genes. The reduced histone acetylation is due to impaired export of mitochondrial acetyl-CoA, owing to the lower levels of citrate carrier (CiC). We demonstrate that aged cells showed enhanced lysosomal degradation of CiC, which is mediated via mitochondrial-derived vesicles. Strikingly, restoring cytosolic acetyl-CoA levels either by exogenous CiC expression or via acetate supplementation, remodels the chromatin landscape and rescues the osteogenesis defects of aged mesenchymal stem cells. Collectively, our results establish a tight, age-dependent connection between mitochondrial quality control, chromatin and stem cell fate, which are linked together by CiC.
    DOI:  https://doi.org/10.1038/s43587-021-00105-8
  28. Nat Aging. 2022 Sep;2(9): 796-808
    Decreased spliceosome fidelity and egl-8 intron retention inhibit mTORC1 signaling to promote longevity.
    Wenming Huang, Chun Kew, Stephanie de Alcantara Fernandes, Anna Löhrke, Lynn Han, Constantinos Demetriades, Adam Antebi.
      Changes in splicing fidelity are associated with loss of homeostasis and aging, yet only a handful of splicing factors have been shown to be causally required to promote longevity, and the underlying mechanisms and downstream targets in these paradigms remain elusive. Surprisingly, we found a hypomorphic mutation within ribonucleoprotein RNP-6/poly(U)-binding factor 60 kDa (PUF60), a spliceosome component promoting weak 3'-splice site recognition, which causes aberrant splicing, elevates stress responses and enhances longevity in Caenorhabditis elegans. Through genetic suppressor screens, we identify a gain-of-function mutation within rbm-39, an RNP-6-interacting splicing factor, which increases nuclear speckle formation, alleviates splicing defects and curtails longevity caused by rnp-6 mutation. By leveraging the splicing changes induced by RNP-6/RBM-39 activities, we uncover intron retention in egl-8/phospholipase C β4 (PLCB4) as a key splicing target prolonging life. Genetic and biochemical evidence show that neuronal RNP-6/EGL-8 downregulates mammalian target of rapamycin complex 1 (mTORC1) signaling to control organismal lifespan. In mammalian cells, PUF60 downregulation also potently and specifically inhibits mTORC1 signaling. Altogether, our results reveal that splicing fidelity modulates lifespan through mTOR signaling.
    DOI:  https://doi.org/10.1038/s43587-022-00275-z
  29. Nat Aging. 2023 Feb;3(2): 144
    T cells proliferate beyond organismal lifespan.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-023-00376-3
  30. Nat Aging. 2022 May;2(5): 377-378
    Healthspan extension in aged mice by cyclic induction of a FOXM1 transgene.
      
    DOI:  https://doi.org/10.1038/s43587-022-00211-1
  31. Nat Aging. 2022 Jan;2(1): 19-30
    Mendelian randomization of genetically independent aging phenotypes identifies LPA and VCAM1 as biological targets for human aging.
    Biobank Japan Project
      Length and quality of life are important to us all, yet identification of promising drug targets for human aging using genetics has had limited success. In the present study, we combine six European-ancestry genome-wide association studies of human aging traits-healthspan, father and mother lifespan, exceptional longevity, frailty index and self-rated health-in a principal component framework that maximizes their shared genetic architecture. The first principal component (aging-GIP1) captures both length of life and indices of mental and physical wellbeing. We identify 27 genomic regions associated with aging-GIP1, and provide additional, independent evidence for an effect on human aging for loci near HTT and MAML3 using a study of Finnish and Japanese survival. Using proteome-wide, two-sample, Mendelian randomization and colocalization, we provide robust evidence for a detrimental effect of blood levels of apolipoprotein(a) and vascular cell adhesion molecule 1 on aging-GIP1. Together, our results demonstrate that combining multiple aging traits using genetic principal components enhances the power to detect biological targets for human aging.
    DOI:  https://doi.org/10.1038/s43587-021-00159-8
  32. Nat Aging. 2023 Apr 17.
    CISH impairs lysosomal function in activated T cells resulting in mitochondrial DNA release and inflammaging.
    Jun Jin, Yunmei Mu, Huimin Zhang, Ines Sturmlechner, Chenyao Wang, Rohit R Jadhav, Qiong Xia, Cornelia M Weyand, Jorg J Goronzy.
      Chronic systemic inflammation is one of the hallmarks of the aging immune system. Here we show that activated T cells from older adults contribute to inflammaging by releasing mitochondrial DNA (mtDNA) into their environment due to an increased expression of the cytokine-inducible SH2-containing protein (CISH). CISH targets ATP6V1A, an essential component of the proton pump V-ATPase, for proteasomal degradation, thereby impairing lysosomal function. Impaired lysosomal activity caused intracellular accumulation of multivesicular bodies and amphisomes and the export of their cargos, including mtDNA. CISH silencing in T cells from older adults restored lysosomal activity and prevented amphisomal release. In antigen-specific responses in vivo, CISH-deficient CD4+ T cells released less mtDNA and induced fewer inflammatory cytokines. Attenuating CISH expression may present a promising strategy to reduce inflammation in an immune response of older individuals.
    DOI:  https://doi.org/10.1038/s43587-023-00399-w
  33. Nat Aging. 2022 Apr;2(4): 285-286
    Human lifespan is linked to truncating variants in single genes.
      
    DOI:  https://doi.org/10.1038/s43587-022-00197-w
  34. Nat Aging. 2022 Aug;2(8): 684-685
    Machine learning to spot frailty in aging mice.
    Elise S Bisset, Susan E Howlett.
      
    DOI:  https://doi.org/10.1038/s43587-022-00267-z
  35. Nat Aging. 2021 Jun;1(6): 500-505
    Achieving a three-dimensional longevity dividend.
    Andrew J Scott.
      Improvements in life expectancy among high-income countries are increasingly occurring in later years. Efforts to exploit the malleability of age and the additional time longevity brings are already underway, but important roadblocks remain. This article discusses the socioeconomic concept of the longevity dividend, in which healthy and productive aging is achieved through a positive correlation between three dimensions: life expectancy, health and the economy. Investing in a longevity dividend is needed to offset the economic challenges of an aging society and embrace a new life course, but this requires deep-seated changes in individual behavior and corporate and government policies. Focusing on treatments that target delayed aging, supporting employment beyond 50 years of age and tackling ageism are key priorities.
    DOI:  https://doi.org/10.1038/s43587-021-00074-y
  36. Nat Aging. 2023 Feb;3(2): 151-152
    Harnessing light energy to charge mitochondria and extend lifespan.
      
    DOI:  https://doi.org/10.1038/s43587-023-00364-7
  37. Nat Aging. 2021 Jul;1(7): 576-578
    Aging Like Struldbruggs, Dorian Gray or Peter Pan.
    S Jay Olshansky.
      
    DOI:  https://doi.org/10.1038/s43587-021-00087-7
  38. Nat Rev Genet. 2023 Apr 28.
    Cryptic initiation drives transcriptional junk in ageing.
    Michael Attwaters.
      
    DOI:  https://doi.org/10.1038/s41576-023-00608-7
  39. Nat Aging. 2022 Mar;2(3): 254-263
    Healthy aging and muscle function are positively associated with NAD+ abundance in humans.
    Georges E Janssens, Lotte Grevendonk, Ruben Zapata Perez, Bauke V Schomakers, Johan de Vogel-van den Bosch, Jan M W Geurts, Michel van Weeghel, Patrick Schrauwen, Riekelt H Houtkooper, Joris Hoeks.
      Skeletal muscle is greatly affected by aging, resulting in a loss of metabolic and physical function. However, the underlying molecular processes and how (lack of) physical activity is involved in age-related metabolic decline in muscle function in humans is largely unknown. Here, we compared, in a cross-sectional study, the muscle metabolome from young to older adults, whereby the older adults were exercise trained, had normal physical activity levels or were physically impaired. Nicotinamide adenine dinucleotide (NAD+) was one of the most prominent metabolites that was lower in older adults, in line with preclinical models. This lower level was even more pronounced in impaired older individuals, and conversely, exercise-trained older individuals had NAD+ levels that were more similar to those found in younger individuals. NAD+ abundance positively correlated with average number of steps per day and mitochondrial and muscle functioning. Our work suggests that a clear association exists between NAD+ and health status in human aging.
    DOI:  https://doi.org/10.1038/s43587-022-00174-3
  40. Nutrients. 2023 Apr 11. pii: 1840. [Epub ahead of print]15(8):
    Nutritional Programming of the Lifespan of Male Drosophila by Activating FOXO on Larval Low-Nutrient Diet.
    Yue Gao, Xingyi Cheng, Yao Tian, Zhixiao Yuan, Xiaolan Fan, Deying Yang, Mingyao Yang.
      Nutrition during the developmental stages has long-term effects on adult physiology, disease and lifespan, and is termed nutritional programming. However, the underlying molecular mechanisms of nutritional programming are not yet well understood. In this study, we showed that developmental diets could regulate the lifespan of adult Drosophila in a way that interacts with various adult diets during development and adulthood. Importantly, we demonstrated that a developmental low-yeast diet (0.2SY) extended both the health span and lifespan of male flies under nutrient-replete conditions in adulthood through nutritional programming. Males with a low-yeast diets during developmental stages had a better resistance to starvation and lessened decline of climbing ability with age in adulthood. Critically, we revealed that the activity of the Drosophila transcription factor FOXO (dFOXO) was upregulated in adult males under developmental low-nutrient conditions. The knockdown of dFOXO, with both ubiquitous and fat-body-specific patterns, can completely abolish the lifespan-extending effect from the larval low-yeast diet. Ultimately, we identify that the developmental diet achieved the nutritional programming of the lifespan of adult males by modulating the activity of dFOXO in Drosophila. Together, these results provide molecular evidence that the nutrition in the early life of animals could program the health of their later life and their longevity.
    Keywords:  Drosophila; dFOXO; lifespan; low-yeast diet; male; nutritional programming
    DOI:  https://doi.org/10.3390/nu15081840
  41. Nat Aging. 2022 Mar;2(3): 182-185
    The energy-splicing resilience axis hypothesis of aging.
    Luigi Ferrucci, David M Wilson, Stefano Donegà, Myriam Gorospe.
      
    DOI:  https://doi.org/10.1038/s43587-022-00189-w
  42. Nat Aging. 2023 Jan;3(1): 47-63
    piRNAs regulate a Hedgehog germline-to-soma pro-aging signal.
    Cheng Shi, Coleen T Murphy.
      The reproductive system regulates somatic aging through competing anti- and pro-aging signals. Germline removal extends somatic lifespan through conserved pathways including insulin and mammalian target-of-rapamycin signaling, while germline hyperactivity shortens lifespan through unknown mechanisms. Here we show that mating-induced germline hyperactivity downregulates piRNAs, in turn desilencing their targets, including the Hedgehog-like ligand-encoding genes wrt-1 and wrt-10, ultimately causing somatic collapse and death. Germline-produced Hedgehog signals require PTR-6 and PTR-16 receptors for mating-induced shrinking and death. Our results reveal an unconventional role of the piRNA pathway in transcriptional regulation of Hedgehog signaling and a new role of Hedgehog signaling in the regulation of longevity and somatic maintenance: Hedgehog signaling is controlled by the tunable piRNA pathway to encode the previously unknown germline-to-soma pro-aging signal. Mating-induced piRNA downregulation in the germline and subsequent Hedgehog signaling to the soma enable the animal to tune somatic resource allocation to germline needs, optimizing reproductive timing and survival.
    DOI:  https://doi.org/10.1038/s43587-022-00329-2
  43. Nat Aging. 2021 Sep;1(9): 783-794
    Rare genetic coding variants associated with human longevity and protection against age-related diseases.
    Regeneron Genetics Center
      Extreme longevity in humans has a strong genetic component, but whether this involves genetic variation in the same longevity pathways as found in model organisms is unclear. Using whole-exome sequences of a large cohort of Ashkenazi Jewish centenarians to examine enrichment for rare coding variants, we found most longevity-associated rare coding variants converge upon conserved insulin/insulin-like growth factor 1 signaling and AMP-activating protein kinase signaling pathways. Centenarians have a number of pathogenic rare coding variants similar to control individuals, suggesting that rare variants detected in the conserved longevity pathways are protective against age-related pathology. Indeed, we detected a pro-longevity effect of rare coding variants in the Wnt signaling pathway on individuals harboring the known common risk allele APOE4. The genetic component of extreme human longevity constitutes, at least in part, rare coding variants in pathways that protect against aging, including those that control longevity in model organisms.
    DOI:  https://doi.org/10.1038/s43587-021-00108-5
  44. Nat Aging. 2023 Feb;3(2): 139-141
    Senescent cells, senolytics and tissue repair: the devil may be in the dosing.
    Sundeep Khosla.
      
    DOI:  https://doi.org/10.1038/s43587-023-00365-6
  45. Exp Gerontol. 2023 Apr 23. pii: S0531-5565(23)00103-1. [Epub ahead of print] 112182
    How does the body know how old it is?
    Josh Mitteldorf.
      Based on the ideas of R. A. Fisher, neoDarwinism came to dominate evolutionary science in the first half of the twentieth century, and within that perspective aging could never be an evolved adaptation. But as the genetic and epigenetic mechanisms of aging came to be elucidated in many species, the signature of an adaptation became clear. Simultaneously, evolutionary theorists were proposing diverse selective mechanisms that might account for adaptations that are beneficial to the community, even as they imposed a fitness cost on the individual. Epigenetic conceptions of aging gained currency with the development of methylation clocks beginning in 2013. The idea that aging is an epigenetic program has propitious implications for the feasibility of medical rejuvenation. It should be easier to intervene in the body's age-related signaling, or even to reprogram the body's epigenetics, compared to brute-force repair of all the physical and chemical damage that accrues with age. The upstream clock mechanism(s) that control the timing of growth, development, and aging remain obscure. I propose that because of the need of all biological systems to be homeostatic, we should expect that aging is controlled by multiple, independent timekeepers. A single point of intervention may be available in the signaling that these clocks use to coordinate information about the age of the body. This may be a way of understanding the successes to date of plasma-based rejuvenation.
    Keywords:  Evolution of aging; Hypothalamus; Methylation; Plasmapheresis; Programmed aging; Suprachiasmatic nucleus
    DOI:  https://doi.org/10.1016/j.exger.2023.112182
  46. Nat Aging. 2023 Mar;3(3): 244-245
    A senolytic strategy integrating multiple technologies delays aging.
      
    DOI:  https://doi.org/10.1038/s43587-023-00369-2
  47. Nat Aging. 2022 Feb;2(2): 97-99
    NAD+ boosting brings tears to aging eyes.
    Mitsukuni Yoshida, Rajendra S Apte.
      
    DOI:  https://doi.org/10.1038/s43587-022-00172-5
  48. Nat Aging. 2022 Oct;2(10): 906-922
    Skin chronological aging drives age-related bone loss via secretion of cystatin-A.
    Wenquan Liang, Qingjing Chen, Shasha Cheng, Ruiming Wei, Yuejun Li, Chenfeng Yao, Zhicong Ouyang, Dawei Kang, Ajuan Chen, Zezheng Liu, Kai Li, Xiaochun Bai, Qingchu Li, Bin Huang.
      Although clinical evidence has indicated an association between skin atrophy and bone loss during aging, their causal relationship and the underlying mechanisms are unknown. Here we show that premature skin aging drives bone loss in mice. We further identify that cystatin-A (Csta), a keratinocyte-enriched secreted factor, mediates the effect of skin on bone. Keratinocyte-derived Csta binds the receptor for activated C-kinase 1 in osteoblast and osteoclast progenitors, thus promoting their proliferation but inhibiting osteoclast differentiation. Csta secretion decreases with skin aging in both mice and humans, thereby causing senile osteoporosis by differentially decreasing the numbers of osteoblasts and osteoclasts. In contrast, topical application of calcipotriol stimulates Csta production in the epidermis and alleviates osteoporosis. These results reveal a mode of endocrine regulation of bone metabolism in the skin, and identify Csta as an epidermally derived hormone linking skin aging to age-related bone loss. Enhancers of skin Csta levels could serve as a potential topical drug for treatment of senile osteoporosis.
    DOI:  https://doi.org/10.1038/s43587-022-00285-x
  49. Trends Cell Biol. 2023 Apr 26. pii: S0962-8924(23)00070-3. [Epub ahead of print]
    The Warburg effect: a signature of mitochondrial overload.
    Yahui Wang, Gary J Patti.
      A long-standing question in cancer biology has been why oxygenated tumors ferment the majority of glucose they consume to lactate rather than oxidizing it in their mitochondria, a phenomenon known as the 'Warburg effect.' An abundance of evidence shows not only that most cancer cells have fully functional mitochondria but also that mitochondrial activity is important to proliferation. It is therefore difficult to rationalize the metabolic benefit of cancer cells switching from respiration to fermentation. An emerging perspective is that rather than mitochondrial metabolism being suppressed in tumors, as is often suggested, mitochondrial activity increases to the level of saturation. As such, the Warburg effect becomes a signature of excess glucose being released as lactate due to mitochondrial overload.
    Keywords:  Warburg effect; aerobic fermentation; aerobic glycolysis; cancer metabolism; mitochondrial metabolism
    DOI:  https://doi.org/10.1016/j.tcb.2023.03.013
  50. Nat Aging. 2023 Jan;3(1): 121-137
    Cell-type-specific aging clocks to quantify aging and rejuvenation in neurogenic regions of the brain.
    Matthew T Buckley, Eric D Sun, Benson M George, Ling Liu, Nicholas Schaum, Lucy Xu, Jaime M Reyes, Margaret A Goodell, Irving L Weissman, Tony Wyss-Coray, Thomas A Rando, Anne Brunet.
      The diversity of cell types is a challenge for quantifying aging and its reversal. Here we develop 'aging clocks' based on single-cell transcriptomics to characterize cell-type-specific aging and rejuvenation. We generated single-cell transcriptomes from the subventricular zone neurogenic region of 28 mice, tiling ages from young to old. We trained single-cell-based regression models to predict chronological age and biological age (neural stem cell proliferation capacity). These aging clocks are generalizable to independent cohorts of mice, other regions of the brains, and other species. To determine if these aging clocks could quantify transcriptomic rejuvenation, we generated single-cell transcriptomic datasets of neurogenic regions for two interventions-heterochronic parabiosis and exercise. Aging clocks revealed that heterochronic parabiosis and exercise reverse transcriptomic aging in neurogenic regions, but in different ways. This study represents the first development of high-resolution aging clocks from single-cell transcriptomic data and demonstrates their application to quantify transcriptomic rejuvenation.
    DOI:  https://doi.org/10.1038/s43587-022-00335-4
  51. Nat Aging. 2023 Feb;3(2): 153-154
    Changes in neurovascular function in brain microvessels during aging.
      
    DOI:  https://doi.org/10.1038/s43587-022-00355-0
  52. Nat Aging. 2022 Jun;2(6): 463-464
    Enhanced brain mitophagy slows systemic aging.
    Sofie Lautrup, Evandro F Fang.
      
    DOI:  https://doi.org/10.1038/s43587-022-00226-8
  53. Nat Aging. 2023 Mar;3(3): 242-243
    Aging breaks liver vascular 'zone defense'.
    Zhongwei Cao, Bi-Sen Ding.
      
    DOI:  https://doi.org/10.1038/s43587-023-00371-8
  54. Nat Aging. 2021 Aug;1(8): 625-627
    Young microbiota rejuvenates the aging brain.
    Rochellys Diaz Heijtz, Ayoze Gonzalez-Santana, Jon D Laman.
      
    DOI:  https://doi.org/10.1038/s43587-021-00100-z
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