1. McCay, C. M., Maynard, L. A., Sperling, G. & Barnes, L. L. Retarded growth, life span, ultimate body size and age changes in the albino rat after feeding diets restricted in calories: four fgures. J. Nutr. 18, 1–13 (1939).
This study shows that the restriction of calories without malnutrition prolongs mean and maximum lifespan in rats compared to ad libitum feeding.
2. Mattison, J. A. et al. Caloric restriction improves health and survival of rhesus monkeys. Nat. Commun. 8, 14063 (2017).
3. Piferi, F. et al. Caloric restriction increases lifespan but afects brain integrity in grey mouse lemur primates. Commun. Biol. 1, 30 (2018).
4. Omodei, D. & Fontana, L. Calorie restriction and prevention of age-associated chronic disease. FEBS Lett. 585, 1537–1542 (2011).
5. Niccoli, T. & Partridge, L. Ageing as a risk factor for disease. Curr. Biol. 22, R741–R752 (2012).
6. Kennedy, B. K. et al. Geroscience: linking aging to chronic disease. Cell 159, 709–713 (2014).
7. Medawar, P. B. An Unsolved Problem of Biology (H. K. Lewis, 1952).
8. Rose, M. & Charlesworth, B. A test of evolutionary theories of senescence. Nature 287, 141–142 (1980).
This study demonstrates that delaying the age of reproduction for several
generations extends lifespan.
9. Friedman, D. B. & Johnson, T. E. A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics 118, 75–86 (1988).
This study describes a C. elegans mutant strain that has an extended lifespan.
10. Kapahi, P. et al. With TOR, less is more: a key role for the conserved nutrient sensing TOR pathway in aging. Cell Metab. 11, 453–465 (2010).
11. Kenyon, C., Chang, J., Gensch, E., Rudner, A. & Tabtiang, R. A C. elegans mutant that lives twice as long as wild type. Nature 366, 461–464 (1993).
This study described that a mutation in the daf-2 gene that enhances dauer formation also extends lifespan.
12. Ogg, S. et al. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389, 994–999 (1997).
13. Fabrizio, P., Pozza, F., Pletcher, S. D., Gendron, C. M. & Longo, V. D. Regulation of longevity and stress resistance by Sch9 in yeast. Science 292, 288–290 (2001).
14. Tatar, M. et al. A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292, 107–110 (2001).
15. Clancy, D. J. et al. Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science 292, 104–106 (2001).
16. Bartke, A. Impact of reduced insulin-like growth factor-1/insulin signaling on aging in mammals: novel fndings. Aging Cell 7, 285–290 (2008).
17. Willcox, B. J. et al. FOXO3A genotype is strongly associated with human longevity. Proc. Natl Acad. Sci. USA 105, 13987–13992 (2008).
18. Heitman, J., Movva, N. R. & Hall, M. N. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253, 905–909 (1991).
19. Mannick, J. B. et al. mTOR inhibition improves immune function in the elderly. Sci. Transl. Med. 6, 268ra179 (2014).
20. Kapahi, P. et al. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol. 14, 885–890 (2004).
This study shows that lifespan extension by dietary restriction in fies is due to inhibtion of the TOR kinase.
21. Kaeberlein, M. et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310, 1193–1196 (2005).
22. Chen, D. et al. Germline signaling mediates the synergistically prolonged longevity produced by double mutations in daf-2 and rsks-1 in C. elegans. Cell
Rep. 5, 1600–1610 (2013).
23. Kapahi, P., Kaeberlein, M. & Hansen, M. Dietary restriction and lifespan: lessons from invertebrate models. Ageing Res. Rev. 39, 3–14 (2017).
24. Kennedy, B. K., Austriaco, N. R. Jr, Zhang, J. & Guarente, L. Mutation in the silencing gene SIR4 can delay aging in S. cerevisiae. Cell 80, 485–496 (1995).
25. Kaeberlein, M., McVey, M. & Guarente, L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two diferent mechanisms. Genes Dev. 13, 2570–2580 (1999).
26. Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000).
27. Lin, S. J., Defossez, P. A. & Guarente, L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289, 2126–2128 (2000).
This study shows that lifespan extension by glucose restriction in yeast requires the activity of Sir2.
28. North, B. J. & Verdin, E. Sirtuins: Sir2-related NAD-dependent protein deacetylases. Genome Biol. 5, 224 (2004).
29. Carrico, C., Meyer, J. G., He, W., Gibson, B. W. & Verdin, E. The mitochondrial acylome emerges: proteomics, regulation by sirtuins, and metabolic and disease implications. Cell Metab. 27, 497–512 (2018).
30. Cohen, H. Y. et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305, 390–392 (2004).
31. Kanf, Y. et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature 483, 218–221 (2012).
32. Satoh, A. et al. Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. Cell Metab. 18, 416–430 (2013).
33. Someya, S. et al. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 143, 802–812 (2010).
34. Cantó, C. et al. AMPK regulates energy expenditure by modulating NAD+metabolism and SIRT1 activity. Nature 458, 1056–1060 (2009).
35. Chen, D. et al. Tissue-specifc regulation of SIRT1 by calorie restriction. Genes Dev. 22, 1753–1757 (2008).
36. Costford, S. R. et al. Skeletal muscle NAMPT is induced by exercise in humans. Am. J. Physiol. Endocrinol. Metab. 298, E117–E126 (2010).
37. Fulco, M. et al. Glucose restriction inhibits skeletal myoblast diferentiation by activating SIRT1 through AMPK-mediated regulation of Nampt. Dev. Cell 14, 661–673 (2008).
38. Nakahata, Y., Sahar, S., Astarita, G., Kaluzova, M. & Sassone-Corsi, P. Circadian control of the NAD+ salvage pathway by CLOCK–SIRT1. Science 324, 654–657 (2009).
39. Ramsey, K. M. et al. Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science 324, 651–654 (2009).
40. Rodgers, J. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434
41. Belenky, P., Bogan, K. L. & Brenner, C. NAD+ metabolism in health and disease. Trends Biochem. Sci. 32, 12–19 (2007).
42. Mouchiroud, L. et al. The NAD+/Sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154, 430–441 (2013).
43. Kondratov, R. V. A role of the circadian system and circadian proteins in aging. Ageing Res. Rev. 6, 12–27 (2007).
44. Katewa, S. D. et al. Peripheral circadian clocks mediate dietary restriction dependent changes in lifespan and fat metabolism in Drosophila. Cell Metab. 23, 143–154 (2016).
45. Patel, S. A., Chaudhari, A., Gupta, R., Velingkaar, N. & Kondratov, R. V. Circadian clocks govern calorie restriction-mediated life span extension through BMAL1- and IGF-1-dependent mechanisms. FASEB J. 30, 1634–1642 (2016).
46. Sato, S. et al. Circadian reprogramming in the liver identifes metabolic pathways of aging. Cell 170, 664–677 (2017).
47. Longo, V. D. & Panda, S. Fasting, circadian rhythms, and time-restricted feeding in healthy lifespan. Cell Metab. 23, 1048–1059 (2016).
48. Harman, D. Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 11, 298–300 (1956).
49. Harman, D. The biologic clock: the mitochondria? J. Am. Geriatr. Soc. 20, 145–147 (1972).
50. Ristow, M. & Zarse, K. How increased oxidative stress promotes longevity and metabolic health: the concept of mitochondrial hormesis (mitohormesis). Exp. Gerontol. 45, 410–418 (2010).
51. Houtkooper, R. H. et al. Mitonuclear protein imbalance as a conserved
longevity mechanism. Nature 497, 451–457 (2013).
52. Dillin, A. et al. Rates of behavior and aging specifed by mitochondrial function
during development. Science 298, 2398–2401 (2002).
53. Lee, S.-J., Hwang, A. B. & Kenyon, C. Inhibition of respiration extends C. elegans life span via reactive oxygen species that increase HIF-1 activity. Curr. Biol. 20, 2131–2136 (2010).
54. Sun, J., Folk, D., Bradley, T. J. & Tower, J. Induced overexpression of mitochondrial Mn-superoxide dismutase extends the life span of adult Drosophila melanogaster. Genetics 161, 661–672 (2002).
55. Tower, J. Transgenic methods for increasing Drosophila life span. Mech. Ageing Dev. 118, 1–14 (2000).
56. Pérez, V. I. et al. The overexpression of major antioxidant enzymes does not extend the lifespan of mice. Aging Cell 8, 73–75 (2009).
57. Lee, H. Y. et al. Mitochondrial-targeted catalase protects against high-fat diet-induced muscle insulin resistance by decreasing intramuscular lipid accumulation. Diabetes 66, 2072–2081 (2017).
58. Dai, D. F. et al. Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation 119, 2789–2797 (2009).
59. Schriner, S. E. et al. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308, 1909–1911 (2005).
60. Brand, M. D. The sites and topology of mitochondrial superoxide production. Exp. Gerontol. 45, 466–472 (2010).
61. Goncalves, R. L., Quinlan, C. L., Perevoshchikova, I. V., Hey-Mogensen, M. & Brand, M. D. Sites of superoxide and hydrogen peroxide production by muscle mitochondria assessed ex vivo under conditions mimicking rest and exercise. J. Biol. Chem. 290, 209–227 (2015).
62. Yun, J. & Finkel, T. Mitohormesis. Cell Metab. 19, 757–766 (2014).
63. Ristow, M. & Schmeisser, S. Extending life span by increasing oxidative stress. Free Radic. Biol. Med. 51, 327–336 (2011).
64. Sun, N., Youle, R. J. & Finkel, T. The mitochondrial basis of aging. Mol. Cell 61, 654–666 (2016).
65. Lee, S. S. et al. A systematic RNAi screen identifes a critical role for mitochondria in C. elegans longevity. Nat. Genet. 33, 40–48 (2003).
66. Durieux, J., Wolf, S. & Dillin, A. The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell 144, 79–91 (2011).
67. Lin, Y. F. & Haynes, C. M. Metabolism and the UPRmt. Mol. Cell 61, 677–682 (2016).
68. Guarente, L. Mitochondria—a nexus for aging, calorie restriction, and sirtuins? Cell 132, 171–176 (2008).
69. Verdin, E. NAD+ in aging, metabolism, and neurodegeneration. Science 350, 1208–1213 (2015).
70. Zid, B. M. et al. 4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila. Cell 139, 149–160 (2009).
71. Hayfick, L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37, 614–636 (1965).
72. Hayfick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961).
73. Coppé, J. P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, e301 (2008).
This paper describes the multi-faceted senescence-associated secretory phenotype, its induction by senescence-inducing stimuli and its potential role in driving both degenerative and hyperplastic diseases of ageing.
74. Shay, J. W. & Wright, W. E. Hayfick, his limit, and cellular ageing. Nat. Rev. Mol. Cell Biol. 1, 72–76 (2000).
75. d’Adda di Fagagna, F. Living on a break: cellular senescence as a DNA-damage response. Nat. Rev. Cancer 8, 512–522 (2008).
76. Rodier, F. et al. Persistent DNA damage signalling triggers senescence associated infammatory cytokine secretion. Nat. Cell Biol. 11, 973–979 (2009).
77. Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006).
78. Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006).
79. Shah, P. P. et al. Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Genes Dev. 27, 1787–1799 (2013).
80. Wiley, C. D. et al. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab. 23, 303–314 (2016).
81. Campisi, J. Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685–705 (2013).
82. Childs, B. G. et al. Senescent cells: an emerging target for diseases of ageing. Nat. Rev. Drug Discov. 16, 718–735 (2017).
83. Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011).
84. Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fbrosis. Cell 134, 657–667 (2008).
85. Bussian, T. J. et al. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562, 578–582 (2018).
86. Chinta, S. J. et al. Cellular senescence is induced by the environmental neurotoxin paraquat and contributes to neuropathology linked to Parkinson’s disease. Cell Rep. 22, 930–940 (2018).
87. Childs, B. G. et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354, 472–477 (2016).
88. Baker, D. J. et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016).
89. Demaria, M. et al. Cellular senescence promotes adverse efects of chemotherapy and cancer relapse. Cancer Discov. 7, 165–176 (2017).
90. Chang, J. et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22, 78–83 (2016).
91. Ogrodnik, M. et al. Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691 (2017).
92. Schafer, M. J. et al. Cellular senescence mediates fbrotic pulmonary disease. Nat. Commun. 8, 14532 (2017).
93. Jeon, O. H. et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med. 23, 775–781 (2017).
94. Farr, J. N. et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 23, 1072–1079 (2017).
95. Kirkland, J. L., Tchkonia, T., Zhu, Y., Niedernhofer, L. J. & Robbins, P. D. The clinical potential of senolytic drugs. J. Am. Geriatr. Soc. 65, 2297–2301 (2017).
96. Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018).
97. Wang, Y. et al. Discovery of piperlongumine as a potential novel lead for the development of senolytic agents. Aging 8, 2915–2926 (2016).
98. Fuhrmann-Stroissnigg, H. et al. Identifcation of HSP90 inhibitors as a novel class of senolytics. Nat. Commun. 8, 422 (2017).
99. Yosef, R. et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat. Commun. 7, 11190 (2016).
100. Franceschi, C. et al. Infamm-aging. An evolutionary perspective on immunosenescence. Ann. NY Acad. Sci. 908, 244–254 (2000).
101. Renz, H. et al. An exposome perspective: early-life events and immune development in a changing world. J. Allergy Clin. Immunol. 140, 24–40 (2017).
102. Sly, P. D. et al. Health consequences of environmental exposures: causal thinking in global environmental epidemiology. Ann. Glob. Health 82, 3–9 (2016).
103. Floreani, A., Leung, P. S. C. & Gershwin, M. E. Environmental basis of autoimmunity. Clin. Rev. Allergy Immunol. 50, 287–300 (2016).
104. Ferrucci, L. & Fabbri, E. Infammageing: chronic infammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 15, 505–522 (2018).
105. Franceschi, C. & Campisi, J. Chronic infammation (infammaging) and its potential contribution to age-associated diseases. J. Gerontol. A 69, S4–S9 (2014).
106. Kleinstreuer, N. C. et al. Phenotypic screening of the ToxCast chemical library to classify toxic and therapeutic mechanisms. Nat. Biotechnol. 32, 583–591 (2014).
107. Barzilai, N., Hufman, D. M., Muzumdar, R. H. & Bartke, A. The critical role of metabolic pathways in aging. 61, 1315–1322 (2012).
108. Fontana, L. Neuroendocrine factors in the regulation of infammation: excessive adiposity and calorie restriction. Exp. Gerontol. 44, 41–45 (2009).
109. Franceschi, C. et al. Infammaging and anti-infammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech. Ageing Dev. 128, 92–105 (2007).
110. Franceschi, C., Ostan, R. & Santoro, A. Nutrition and infammation: are centenarians similar to individuals on calorie-restricted diets? Annu. Rev. Nutr. 38, 329–356 (2018).
111. Pérez, V. I. et al. Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat. Proc. Natl Acad. Sci. USA 106, 3059–3064 (2009).
112. Treaster, S. B. et al. Superior proteome stability in the longest lived animal. Age36, 9597 (2013).
113. Kaushik, S. & Cuervo, A. M. Proteostasis and aging. Nat. Med. 21, 1406–1415 (2015).
114. Reis-Rodrigues, P. et al. Proteomic analysis of age-dependent changes in protein solubility identifes genes that modulate lifespan. Aging Cell 11, 120–127 (2012).
115. David, D. C. et al. Widespread protein aggregation as an inherent part of aging in C. elegans. PLoS Biol. 8, e1000450 (2010).
116. Klaips, C. L., Jayaraj, G. G. & Hartl, F. U. Pathways of cellular proteostasis in aging and disease. J. Cell Biol. 217, 51–63 (2018).
117. Fabbri, E. et al. Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. J. Am. Med. Dir. Assoc. 16, 640–647 (2015).
118. Kane, A. E. & Sinclair, D. A. Sirtuins and NAD+ in the development and treatment of metabolic and cardiovascular diseases. Circ. Res. 123, 868–885 (2018).
119. St Sauver, J. L. et al. Risk of developing multimorbidity across all ages in an historical cohort study: diferences by sex and ethnicity. BMJ Open 5, e006413 (2015).
120. Kaplan-Lewis, E., Aberg, J. A. & Lee, M. Aging with HIV in the ART era. Semin. Diagn. Pathol. 34, 384–397 (2017).
121. Brown, R. T. et al. Geriatric conditions in a population-based sample of older homeless adults. Gerontologist 57, 757–766 (2017).
122. Olshansky, S. J., Carnes, B. A. & Cassel, C. In search of Methuselah: estimating the upper limits to human longevity. Science 250, 634–640 (1990).
123. Ismail, K. et al. Compression of morbidity is observed across cohorts with exceptional longevity. J. Am. Geriatr. Soc. 64, 1583–1591 (2016).
124. American Geriatrics Society Expert Panel on the Care of Older Adults with Multimorbidity. Guiding principles for the care of older adults with multimorbidity: an approach for clinicians. J. Am. Geriatr. Soc. 60, E1–E25 (2012).
125. Steinman, M. A. Polypharmacy—time to get beyond numbers. JAMA Intern. Med. 176, 482–483 (2016).
126. Fried, L. P. et al. Frailty in older adults: evidence for a phenotype. J. Gerontol. A56, M146–M157 (2001).
127. Clegg, A., Young, J., Ilife, S., Rikkert, M. O. & Rockwood, K. Frailty in elderly people. Lancet 381, 752–762 (2013).
128. Lai, J. C. et al. Development of a novel frailty index to predict mortality in patients with end-stage liver disease. Hepatology 66, 564–574 (2017).
129. Kim, S. W. et al. Multidimensional frailty score for the prediction of postoperative mortality risk. JAMA Surg. 149, 633–640 (2014).
130. Wallace, L. M. K. et al. Investigation of frailty as a moderator of the relationship between neuropathology and dementia in Alzheimer’s disease: a cross sectional analysis of data from the Rush Memory and Aging Project. Lancet Neurol. 18, 177–184 (2019).
131. Liao, C. Y., Rikke, B. A., Johnson, T. E., Diaz, V. & Nelson, J. F. Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. Aging Cell 9, 92–95 (2010).
132. Wilson, K. A., Nelson, C. S., Beck, J. N., Brem, R. B. & Kapahi, P. Genome-wide analysis reveals distinct genetic mechanisms of diet-dependent lifespan and healthspan in D. melanogaster. Preprint at https://www.biorxiv.org/content/10.1101/153791v2 (2018).
133. Shinohara, M. et al. APOE2 eases cognitive decline during aging: clinical and preclinical evaluations. Ann. Neurol. 79, 758–774 (2016).
134. Garatachea, N. et al. ApoE gene and exceptional longevity: insights from three independent cohorts. Exp. Gerontol. 53, 16–23 (2014).
135. Partridge, L., Deelen, J. & Slagboom, P. E. Facing up to the global challenges of ageing. Nature 561, 45–56 (2018).
136. TenNapel, M. J. et al. SIRT6 minor allele genotype is associated with >5-year decrease in lifespan in an aged cohort. PLoS ONE 9, e115616 (2014).
137. Harper, J. M., Leathers, C. W. & Austad, S. N. Does caloric restriction extend life in wild mice? Aging Cell 5, 441–449 (2006).
138. Swindell, W. R. Dietary restriction in rats and mice: a meta-analysis and review of the evidence for genotype-dependent efects on lifespan. Ageing Res. Rev. 11, 254–270 (2012).
139. Mattison, J. A. et al. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 489, 318–321 (2012).
140. Olson, M. V. Human genetic individuality. Annu. Rev. Genomics Hum. Genet. 13, 1–27 (2012).
141. Lucanic, M. et al. Impact of genetic background and experimental reproducibility on identifying chemical compounds with robust longevity efects. Nat. Commun. 8, 14256 (2017).
142. Richardson, A. et al. Measures of healthspan as indices of aging in mice—a recommendation. J. Gerontol. A 71, 427–430 (2016).
143. Fischer, K. E. et al. A cross-sectional study of male and female C57BL/6Nia mice suggests lifespan and healthspan are not necessarily correlated. Aging 8, 2370–2391 (2016).
144. Pincus, Z., Smith-Vikos, T. & Slack, F. J. MicroRNA predictors of longevity in Caenorhabditis elegans. PLoS Genet. 7, e1002306 (2011).
145. Zhang, W. B. et al. Extended twilight among isogenic C. elegans causes a disproportionate scaling between lifespan and health. Cell Syst. 3, 333–345 (2016).
146. Bansal, A., Zhu, L. J., Yen, K. & Tissenbaum, H. A. Uncoupling lifespan and healthspan in Caenorhabditis elegans longevity mutants. Proc. Natl Acad. Sci. USA 112, E277–E286 (2015).
147. Nadon, N. L., Strong, R., Miller, R. A. & Harrison, D. E. NIA interventions testing program: investigating putative aging intervention agents in a genetically heterogeneous mouse model. EBioMedicine 21, 3–4 (2017).
148. Zaseck, L. W., Miller, R. A. & Brooks, S. V. Rapamycin attenuates age-associated changes in tibialis anterior tendon viscoelastic properties. J. Gerontol. A 71, 858–865 (2016).
149. Flynn, J. M. et al. Late-life rapamycin treatment reverses age-related heart dysfunction. Aging Cell 12, 851–862 (2013).
150. Lin, A. L. et al. Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer’s disease. J. Cereb. Blood Flow Metab. 33, 1412–1421 (2013).
151. Martin-Montalvo, A. et al. Metformin improves healthspan and lifespan in mice. Nat. Commun. 4, 2192 (2013).
152. Mercken, E. M. et al. SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle mass. Aging Cell 13, 787–796 (2014).
153. Mitchell, S. J. et al. The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet. Cell Rep. 6, 836–843 (2014).
154. Justice, J. et al. Frameworks for proof-of-concept clinical trials of interventions that target fundamental aging processes. J. Gerontol. A 71, 1415–1423 (2016). Consensus report from the multidisciplinary Geroscience Network describing clinical trial designs to test novel ageing interventions.
155. Makary, M. A. et al. Frailty as a predictor of surgical outcomes in older patients. J. Am. Coll. Surg. 210, 901–908 (2010).
156. Studenski, S. et al. Gait speed and survival in older adults. J. Am. Med. Assoc. 305, 50–58 (2011).
157. Melis, R., Marengoni, A., Angleman, S. & Fratiglioni, L. Incidence and predictors of multimorbidity in the elderly: a population-based longitudinal study. PLoS ONE 9, e103120 (2014).158. Barzilai, N., Crandall, J. P., Kritchevsky, S. B. & Espeland, M. A. Metformin as a tool to target aging. Cell Metab. 23, 1060–1065 (2016).
159. Bannister, C. A. et al. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes. Metab. 16, 1165–1173 (2014).
160. UK Prospective Diabetes Study (UKPDS) Group. Efect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352, 854–865 (1998).
161. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 346, 393–403 (2002).
162. Justice, J. N. et al. A framework for selection of blood-based biomarkers for geroscience-guided clinical trials: report from the TAME Biomarkers Workgroup. Geroscience 40, 419–436 (2018).
163. Bitto, A. et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. eLife 5, e16351 (2016).
164. Anisimov, V. N. et al. Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle 10, 4230–4236 (2011).
165. Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).
166. Urfer, S. R. et al. A randomized controlled trial to establish efects of short-term rapamycin treatment in 24 middle-aged companion dogs. Geroscience 39, 117–127 (2017).
167. Mannick, J. B. et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci. Transl. Med. 10, eaaq1564 (2018). One of the frst examples of a randomized control trial using ageing targeting drugs in the elderly to treat a clinical syndrome of ageing.
168. Bonkowski, M. S. & Sinclair, D. A. Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nat. Rev. Mol. Cell Biol. 17, 679–690 (2016).
169. Dai, H., Sinclair, D. A., Ellis, J. L. & Steegborn, C. Sirtuin activators and inhibitors: promises, achievements, and challenges. Pharmacol. Ther. 188, 140–154 (2018).
170. Martens, C. R. et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat. Commun. 9, 1286 (2018).
171. Duggal, N. A., Pollock, R. D., Lazarus, N. R., Harridge, S. & Lord, J. M. Major features of immunesenescence, including reduced thymic output, are ameliorated by high levels of physical activity in adulthood. Aging Cell 17, e12750 (2018).
172. Pollock, R. D. et al. Properties of the vastus lateralis muscle in relation to age and physiological function in master cyclists aged 55–79 years. Aging Cell 17, e12735 (2018).
173. Chakravarty, E. F., Hubert, H. B., Lingala, V. B. & Fries, J. F. Reduced disability and mortality among aging runners: a 21-year longitudinal study. Arch. Intern. Med. 168, 1638–1646 (2008).
174. Moore, S. C. et al. Leisure time physical activity of moderate to vigorous intensity and mortality: a large pooled cohort analysis. PLoS Med. 9, e1001335 (2012).
175. Lee, D. C. et al. Running as a key lifestyle medicine for longevity. Prog. Cardiovasc. Dis. 60, 45–55 (2017).
176. Katz, D. L. & Meller, S. Can we say what diet is best for health? Annu. Rev. Public Health 35, 83–103 (2014).
177. Longo, V. D. & Mattson, M. P. Fasting: molecular mechanisms and clinical applications. Cell Metab. 19, 181–192 (2014).
178. Brandhorst, S. et al. A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan. Cell Metab. 22, 86–99 (2015).
179. Hatori, M. et al. Time-restricted feeding without reducing caloric intakrevents metabolic diseases in mice fed a high-fat diet. Cell Metab. 15, 848–860 (2012). This study reports the efects on the healthspan of time-restricted feeding without calorie restriction.
180. Newman, J. C. et al. Ketogenic diet reduces midlife mortality and improves memory in aging mice. Cell Metab. 26, 547–557 (2017). These two papers180,181 report the healthspan-enhancing efect of a ketogenic diet in mice.
181. Roberts, M. N. et al. A ketogenic diet extends longevity and healthspan in adult mice. Cell Metab. 26, 539–546 (2017).
182. Newman, J. C. & Verdin, E. β-Hydroxybutyrate: a signaling metabolite. Annu. Rev. Nutr. 37, 51–76 (2017).
183. Shimazu, T. et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211–214 (2013).
This study shows that β-hydroxybutyrate is an epigenetic regulator that
184. Savji, N. et al. Association between advanced age and vascular disease in diferent arterial territories: a population database of over 3.6 million subjects. J. Am. Coll. Cardiol. 61, 1736–1743 (2013).
185. Xia, X., Chen, W., McDermott, J. & Han, J. J. Molecular and phenotypic biomarkers of aging. F1000 Res. 6, 860 (2017).
186. Levine, M. E. et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging 10, 573–591 (2018).
187. Horvath, S. & Raj, K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat. Rev. Genet. 19, 371–384 (2018).
188. Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 14, R115 (2013).
A report of an epigenetic clock for ageing that is based on diferential DNA methylation.
189. Chaudhuri, J. et al. The role of advanced glycation end products in aging and metabolic diseases: bridging association and causality. Cell Metab. 28, 337–352 (2018).
190. Semba, R. D., Nicklett, E. J. & Ferrucci, L. Does accumulation of advanced glycation end products contribute to the aging phenotype? J. Gerontol. A 65A, 963–975 (2010).
191. Belsky, D. W., Hufman, K. M., Pieper, C. F., Shalev, I. & Kraus, W. E. Change in the rate of biological aging in response to caloric restriction: CALERIE biobank analysis. J. Gerontol. A 73, 4–10 (2018).
192. Dong, X., Milholland, B. & Vijg, J. Evidence for a limit to human lifespan. Nature 538, 257–259 (2016).
This paper argues that there is at present no evidence that the maximum life span of humans (and by inference other complex, as opposed to simple, organisms) is malleable.
193. López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).
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