Is Aging as Inevitable as Death and Taxes?

We all—more or less—think about aging, and our ancestors did too. In Greek mythology, the god of old age, Geras, was often depicted as a shriveled-up old man holding a cane, while the goddess of youth, Hebe, was the young woman keeper of the Fountain of Youth. When we think of aging, even though life expectancy has gone up, it is the increased risk for maladies such as cardiovascular disease, cancer, diabetes, sarcopenia, osteoporosis, and cognitive decline that is more worrisome than the end point.The Authors a Few Years BackView Large Image | View Hi-Res Image | Download PowerPoint SlideWhat makes us age, and can we promote healthy aging? For this Special Issue of Cell Metabolism on Aging, we feature primary research articles and a collection of Crosstalk, Review, Perspective, and Essay articles in aging biology. We hope that this selection will kick-start insightful discussions that we can continue at our upcoming Cell Symposium “Aging and Metabolism” in Spain (July 10–12). We are including a sneak preview of thoughts from the meeting speakers, as well as other leaders in the aging field, in our Voices article.The animal kingdom is full of surprises when it comes to longevity. For example, the naked mole rat, the longest-lived rodent, can live up to 28 years, and the bowhead whale, at 200 years, has the longest lifespan of all animals. Clues into healthy aging may also come from elephants, which carry multiple copies of the tumor-suppressor gene TP53 in their genomes, offering an explanation for their very low cancer rate (Abegglen et al., 2015xPotential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans. Abegglen, L.M., Caulin, A.F., Chan, A., Lee, K., Robinson, R., Campbell, M.S., Kiso, W.K., Schmitt, D.L., Waddell, P.J., Bhaskara, S. et al. JAMA. 2015; 314: 1850–1860Crossref | Scopus (19)See all ReferencesAbegglen et al., 2015). Tissue metabolites across 26 mammalian species, representing ten taxonomical orders, were investigated in a Cell Metabolism study in order to identify metabolites correlating with species lifespan (Ma et al., 2015xOrganization of the Mammalian Metabolome according to Organ Function, Lineage Specialization, and Longevity. Ma, S., Yim, S.H., Lee, S.G., Kim, E.B., Lee, S.R., Chang, K.T., Buffenstein, R., Lewis, K.N., Park, T.J., Miller, R.A. et al. Cell Metab. 2015; 22: 332–343Abstract | Full Text | Full Text PDF | PubMed | Scopus (6)See all ReferencesMa et al., 2015). On the other hand, the African turquoise killifish helps us understand the genetics of accelerating aging (Valenzano et al., 2015xThe African turquoise killifish genome provides insights into evolution and genetic architecture of lifespan. Valenzano, D.R., Benayoun, B.A., Singh, P.P., Zhang, E., Etter, P.D., Hu, C.K., Clement-Ziza, M., Willemsen, D., Cui, R., Harel, I. et al. Cell. 2015; 163: 1539–1554Abstract | Full Text | Full Text PDF | PubMed | Scopus (10)See all ReferencesValenzano et al., 2015). In humans, while progeroid syndromes have taught us how specific gene mutations can dramatically shorten lifespan, the basis for exceptional longevity in centenarians has proven to be much more complex, involving numerous genetic variants, reflecting the interaction with environmental factors.Historically, model organisms, including yeast, worms, and fruit flies, have been instrumental in identifying some of the key genes and signaling pathways regulating lifespan. The past decades have witnessed a rejuvenation of the aging field as new molecular targets underlying the biology of aging have emerged, such as sirtuins and mTOR. These fundamental genetic and epigenetic drivers are conserved across the animal kingdom from yeast to humans and have revealed how intricately intertwined metabolism and aging are. Barzilai and colleagues discuss the complexity of the somatotrophic axis in aging in their Review article, while Kennedy and Lamming provide an update on mTOR, a key hub linking metabolism and aging. Using C. elegans as a model in their research article, Kenyon and colleagues explore the link between starvation-induced quiescence, proteostasis, and aging (Roux et al., 2016xProlonged C. elegans Larval Quiescence Induces Signs of Aging that Can Be Reversed by ire-1-Dependent Pathways. Roux, A.E., Langhans, K., Huynh, W., and Kenyon, C. Cell Metab. 2016; 23: 1113–1126Abstract | Full Text | Full Text PDFSee all ReferencesRoux et al., 2016). Steffen and Dillin pick up this topic further and discuss how changes in translation affect proteostasis and longevity, while Wiley and Campisi delve into the connections between metabolism and cellular senescence.Given its multifactorial nature, aging may well be the most complex physiological question. How do genetics, diet, and other lifestyle factors interact to affect longevity? A critical element underlying this trifecta is the influence of sex on biology, as exemplified by the recent NIH mandate to “consider sex as a biological variable” that needs to “be factored into research designs, analyses, and reporting” (NIH notice NOT-OD-15-102, Consideration of Sex as a Biological Variable in NIH-funded Research). Throughout this Special Issue, several authors, such as deCabo and colleagues, who look at the effects of sex and genetics in response to calorie restriction, emphasize how fundamental this point is (Mitchell et al., 2016xEffects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice. Mitchell, S.J., Madrigal-Matute, J., Scheibye-Knudsen, M., Fang, E., Aon, M., Gonzalez-Reyes, J.A., Cortassa, S., Kaushik, S., Gonzalez-Freire, M., Patel, B. et al. Cell Metab. 2016; 23: 1093–1112Abstract | Full Text | Full Text PDFSee all ReferencesMitchell et al., 2016). In this vein, Fisher and Austad review sex differences in lifespan and conclude that, though more physically limited than men, women are the longer-lived sex. Could the physical limitations be, at least in part, due to skeletal muscle atrophy? Zierath and colleagues offer intriguing answers in their Review about healthy muscle aging. Karsenty and colleagues investigate bone-muscle communication and identify osteocalcin as a strength-promoting hormone that naturally declines with age (Mera et al., 2016xOsteocalcin Signaling in Myofibers Is Necessary and Sufficient for Optimum Adaptation to Exercise. Mera, P., Laue, K., Ferron, M., Confavreux, C., Wei, J., Galan-Diez, M., Lacampagne, A., Mitchell, S.J., Mattison, J.A., Chen, Y. et al. Cell Metab. 2016; 23: 1078–1092Abstract | Full Text | Full Text PDFSee all ReferencesMera et al., 2016). Using a novel mass spectrometry assay, LeBrasseur and colleagues show that the previously thought putative rejuvenating factor, GDF11, does not decrease during aging in humans and, if anything, has a negative health association in older adults with cardiovascular disease (Schafer et al., 2016xQuantification of GDF11 and Myostatin in Human Aging and Cardiovascular Disease. Schafer, M.J., Atkinson, E.J., Vanderboom, P.M., Kotajarvi, B., White, T.A., Moore, M.M., Bruce, C.J., Greason, K.L., Suri, R.M., Khosla, S. et al. Cell Metab. 2016; 23: 1207–1215Abstract | Full Text | Full Text PDF | PubMedSee all ReferencesSchafer et al., 2016). Could the “Fountain of Youth” be “just down the street at your nearest neighborhood gym” as posited by Zierath and colleagues? Not so fast, say Longo and Panda in their Perspective, as “everyday dietary choices can clearly accelerate aging” and “increase the incidence of age-related diseases.”The growing number of insights into what makes us age has led some to investigate ways to slow the process down. Considerable pharmaceutical and biotech research efforts are currently being focused in this direction such as Kronos Longevity Research, Proteostasis Therapeutics, and Calico, to name a few, not only looking into novel therapeutics, but also revisiting old ones such as hormonal treatments and antioxidants. The immunosuppressant rapamycin, which is one of the first drugs shown to extend lifespan in a variety of species, including mammals, is currently being tested in a clinical trial for the treatment of Hutchinson-Gilford progeria syndrome. In their Essay, Barzilai and colleagues explain why they chose the anti-diabetic drug metformin for their Targeting Aging with Metformin (TAME) clinical trial of 65+ humans as a paradigm for the evaluation of pharmacological approaches to combat aging. Coming back to diet as a therapy, Elysium Health markets nutritional supplements (nutraceuticals) aimed at boosting NAD levels. Intriguing research in this issue by Chini and colleagues identifies CD38 as the enzyme responsible for the age-related decline in endogenous NAD levels and shows that CD38 can modulate the response to NAD replacement therapies in mice.So it looks like there’s hope for Geras after all; he might soon be able to ditch his cane, spend less time worrying about his health, and post more selfies while skateboarding. Rock on!