The Four Layers of Aging
2015; Elsevier BV; Volume: 1; Issue: 3 Linguagem: Inglês
10.1016/j.cels.2015.09.002
ISSN2639-5460
AutoresRan Zhang, Hou‐Zao Chen, De‐Pei Liu,
Tópico(s)Aging, Elder Care, and Social Issues
ResumoInstead of considering aging in terms of discrete hallmarks, we suggest that it operates in four layers, each at a different biological scale. Malfunctions within each layer—and connections between them—produce the aged phenotype and its associated susceptibility to disease. Instead of considering aging in terms of discrete hallmarks, we suggest that it operates in four layers, each at a different biological scale. Malfunctions within each layer—and connections between them—produce the aged phenotype and its associated susceptibility to disease. The defining feature of the last period of life, aging is characterized by the progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. A full understanding of the aging as a process, however, is greatly impeded by its complexity. Geroscience studies the genetic and environmental contributions to diseases associated with aging; the goal is a mechanistic understanding of these relationships at the molecular, network, and systems levels. A large number of aging mechanisms have been proposed, including maladaptive chronic inflammation, oxidative stress, cellular senescence, and genome instability (Balaban et al., 2005Balaban R.S. Nemoto S. Finkel T. Mitochondria, oxidants, and aging.Cell. 2005; 120: 483-495Abstract Full Text Full Text PDF PubMed Scopus (3286) Google Scholar, Campisi, 2013Campisi J. Aging, cellular senescence, and cancer.Annu. Rev. Physiol. 2013; 75: 685-705Crossref PubMed Scopus (1651) Google Scholar, Franceschi et al., 2007Franceschi C. Capri M. Monti D. Giunta S. Olivieri F. Sevini F. Panourgia M.P. Invidia L. Celani L. Scurti M. et al.Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans.Mech. Ageing Dev. 2007; 128: 92-105Crossref PubMed Scopus (1460) Google Scholar, Vijg and Suh, 2013Vijg J. Suh Y. Genome instability and aging.Annu. Rev. Physiol. 2013; 75: 645-668Crossref PubMed Scopus (241) Google Scholar). Many studies emphasize these different manifestations of aging as discrete processes and largely neglect their inherent connections. Here, instead of considering aging as a set of isolated processes, we discuss aging in terms of “four layers,” each at a different biological scale. From an overall phenotype to a molecular mechanism, the four layers of aging are as follows: the organism’s decline in physical function and increased susceptibility to diseases (layer 1); systemic immune, metabolic, and endocrine dysfunction (layer 2); cellular malfunction (layer 3); and failure of biomolecule maintenance (layer 4). In this context, we briefly discuss the problems of disentangling cause from consequence in aging, speak to the question of aging as a developmental program, and evaluate strategies for treating age-related diseases. The most obvious layer of aging, layer 1, is the organism’s overall physical deterioration, functional decline, and increased susceptibility to age-related diseases (Figure 1A). Age-associated organismal degeneration is concomitant with tissue-level changes in cell number and composition. For example, the wasting of tissues during age is ubiquitous and frequently attributed to stem cell depletion. By contrast, cancer presents as a unique class of age-related diseases, which are characterized by uncontrolled cellular proliferation rather than cellular loss. While age-related diseases appear to be independent and diverse from the perspective of layer 1, their inherent connections are revealed in layers two through four. Layer 2 comprises the systems that regulate the body’s physiology. It links cellular level changes, like the production of cytokines, to organism-level phenotypes, like cardiovascular diseases and cancers. Here, we focus on chronic inflammation, metabolic deregulation resulting from aberrant nutrient-sensing, and endocrine dysfunction as examples of systems found in this layer (Figure 1B). Under normal, adaptive physiological conditions, inflammation helps clear pathogens and heals wounded tissues. However, the chronic low-grade inflammation that develops during aging contributes to the onset and development of age-related diseases. This relationship was established by studies that inhibited inflammation and observed that this intervention protects against age-related diseases. For example, genetic inhibition of the inflammatory nuclear factor (NF)-κB pathway attenuates amyotrophy, insulin resistance, and neurodegeneration and prolongs the lifespan of mice (Cai et al., 2004Cai D. 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Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH.Nature. 2013; 497: 211-216Crossref PubMed Scopus (596) Google Scholar). Likewise, ablation of the Nlrp3 inflammasome protects mice from age-related astrogliosis, glucose intolerance, bone loss, and thymic involution (Youm et al., 2013Youm Y.H. Grant R.W. McCabe L.R. Albarado D.C. Nguyen K.Y. Ravussin A. Pistell P. Newman S. Carter R. Laque A. et al.Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging.Cell Metab. 2013; 18: 519-532Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar). Recently, type I interferon (IFN-I) signaling was reported to increase in the choroid plexus upon aging, and blocking IFN-I signaling in the aged brain alleviates cognitive decline (Baruch et al., 2014Baruch K. Deczkowska A. David E. Castellano J.M. Miller O. Kertser A. Berkutzki T. Barnett-Itzhaki Z. Bezalel D. Wyss-Coray T. et al.Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function.Science. 2014; 346: 89-93Crossref PubMed Scopus (349) Google Scholar). Due to the intimate relationship between inflammation and aging, the neologism “inflammaging” is frequently used to describe the low-grade pro-inflammatory patient status seen in old age. Given these studies and similar ones, it can be inferred that the body’s own inflammatory response either causes age-related diseases directly or makes them more likely in older individuals. In addition to chronic inflammation, another age-associated systemic change is metabolic dysfunction. To date, it has been inferred that four conserved nutrient-sensing pathways are deregulated in old individuals; correcting this disregulation with diet or caloric restriction promotes longevity and health. The four pathways are: (1) Insulin/insulin-like growth factor (IGF)-1 signaling (IIS). The best-characterized aging pathway is the IIS pathway (Kenyon et al., 1993Kenyon C. Chang J. Gensch E. Rudner A. Tabtiang R. A C. elegans mutant that lives twice as long as wild type.Nature. 1993; 366: 461-464Crossref PubMed Scopus (2486) Google Scholar); downregulation of the IIS prolongs the lifespan in diverse species. (2) Sirtuins. Sirtuins are a family of NAD+ dependent protein deacylases and ADP ribosyltransferases. Consistent with the pro-survival effects of sirtuins in yeast, worms, and flies, Sirt6 transgenic mice (Kanfi et al., 2012Kanfi Y. Naiman S. Amir G. Peshti V. Zinman G. Nahum L. Bar-Joseph Z. Cohen H.Y. The sirtuin SIRT6 regulates lifespan in male mice.Nature. 2012; 483: 218-221Crossref PubMed Scopus (777) Google Scholar) and brain-specific Sirt1-overexpressing mice (Satoh et al., 2013Satoh A. Brace C.S. Rensing N. Cliften P. Wozniak D.F. Herzog E.D. Yamada K.A. Imai S. 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AMPK modulates tissue and organismal aging in a non-cell-autonomous manner.Cell Rep. 2014; 8: 1767-1780Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar). (4) Mechanistic target of rapamycin (mTOR). The mTOR pathway is activated by nutrients (e.g., amino acids) or hormonal cues (e.g., insulin and growth factors). The downregulation of mTOR universally extends the lifespan of model organisms, including mammals (Harrison et al., 2009Harrison D.E. Strong R. Sharp Z.D. Nelson J.F. Astle C.M. Flurkey K. Nadon N.L. Wilkinson J.E. Frenkel K. Carter C.S. et al.Rapamycin fed late in life extends lifespan in genetically heterogeneous mice.Nature. 2009; 460: 392-395Crossref PubMed Scopus (2695) Google Scholar). These examples highlight the intimate connection between metabolism, intracellular signal transduction, and the lifespan of the organism. They demonstrate that metabolic deregulation and aberrant nutrient-sensing are a prominent feature of aging. As discussed earlier, the ablation of key intermediates in the IIS pathway extends the lifespan (Kenyon et al., 1993Kenyon C. Chang J. Gensch E. Rudner A. Tabtiang R. A C. elegans mutant that lives twice as long as wild type.Nature. 1993; 366: 461-464Crossref PubMed Scopus (2486) Google Scholar). This result led researchers to infer that the sustained elevation of the IIS axis ages individuals prematurely. However, other hormones have the opposite effect. Oxytocin, a neurohypophysial hormone, has also been found to decrease with age and is required for muscle maintenance and regeneration (Elabd et al., 2014Elabd C. Cousin W. Upadhyayula P. Chen R.Y. Chooljian M.S. Li J. Kung S. Jiang K.P. Conboy I.M. Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration.Nat. Commun. 2014; 5: 4082Crossref PubMed Scopus (259) Google Scholar). Similarly, muscle-derived cytokines (myokines), many of which can be induced by physical activity, also protect against aging. For example, a recent report showed that muscle-derived Myoglianin extends the lifespan of Drosophila (Demontis et al., 2014Demontis F. Patel V.K. Swindell W.R. Perrimon N. Intertissue control of the nucleolus via a myokine-dependent longevity pathway.Cell Rep. 2014; 7: 1481-1494Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar) and growth differentiation factor (GDF) 11, a mammalian Myoglianin ortholog, may be one key to the rejuvenating effects seen in parabiosis experiments (Katsimpardi et al., 2014Katsimpardi L. Litterman N.K. Schein P.A. Miller C.M. Loffredo F.S. Wojtkiewicz G.R. Chen J.W. Lee R.T. Wagers A.J. Rubin L.L. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors.Science. 2014; 344: 630-634Crossref PubMed Scopus (672) Google Scholar, Loffredo et al., 2013Loffredo F.S. Steinhauser M.L. Jay S.M. 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Through the IKK/NF-κB and JNK/AP1 pathways, chronic inflammation represses insulin sensitivity and reduces the utilization of nutrients by peripheral tissues (Han et al., 2013Han M.S. Jung D.Y. Morel C. Lakhani S.A. Kim J.K. Flavell R.A. Davis R.J. JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation.Science. 2013; 339: 218-222Crossref PubMed Scopus (479) Google Scholar, Wang et al., 2014Wang X.A. Zhang R. She Z.G. Zhang X.F. Jiang D.S. Wang T. Gao L. Deng W. Zhang S.M. Zhu L.H. et al.Interferon regulatory factor 3 constrains IKKβ/NF-κB signaling to alleviate hepatic steatosis and insulin resistance.Hepatology. 2014; 59: 870-885Crossref PubMed Scopus (111) Google Scholar). Consequently, excess nutrients accumulate and contribute to low-grade inflammation (Shi et al., 2006Shi H. Kokoeva M.V. Inouye K. Tzameli I. Yin H. Flier J.S. TLR4 links innate immunity and fatty acid-induced insulin resistance.J. Clin. 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