The Spectrum of Fundamental Basic Science Discoveries Contributing to Organismal Aging

Abstract

Aging research has undergone unprecedented advances at an accelerating rate in recent years, leading to excitement in the field as well as opportunities for imagination and innovation. Novel insights indicate that, rather than resulting from a preprogrammed series of events, the aging process is predominantly driven by fundamental non-adaptive mechanisms that are interconnected, linked, and overlap. To varying degrees, these mechanisms also manifest with aging in bone where they cause skeletal fragility. Because these mechanisms of aging can be manipulated, it might be possible to slow, delay, or alleviate multiple age-related diseases and their complications by targeting conserved genetic signaling pathways, controlled functional networks, and basic biochemical processes. Indeed, findings in various mammalian species suggest that targeting fundamental aging mechanisms (eg, via either loss-of-function or gain-of-function mutations or administration of pharmacological therapies) can extend healthspan; ie, the healthy period of life free of chronic diseases. In this review, we summarize the evidence supporting the role of the spectrum of fundamental basic science discoveries contributing to organismal aging, with emphasis on mammalian studies and in particular aging mechanisms in bone that drive skeletal fragility. These mechanisms or aging hallmarks include: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Because these mechanisms are linked, interventions that ameliorate one hallmark can in theory ameliorate others. In the field of bone and mineral research, current challenges include defining the relative contributions of each aging hallmark to the natural skeletal aging process, better understanding the complex interconnections among the hallmarks, and identifying the most effective therapeutic strategies to safely target multiple hallmarks. Based on their interconnections, it may be feasible to simultaneously interfere with several fundamental aging mechanisms to alleviate a wide spectrum of age-related chronic diseases, including osteoporosis. © 2018 American Society for Bone and Mineral Research.

Sirtuins and FoxOs in osteoporosis and osteoarthritis

“…This premise is further substantiated by findings that Sirt1 stimulators attenuate osteoporosis and osteoarthritis in different disease models. Exciting recent discoveries have elucidated that common mechanisms of aging such as oxidative stress and cellular senescence contribute to skeletal involution and osteoarthritis [111,157]. It is, therefore, critical to continue the search for mechanisms of skeletal aging so that both osteoporosis and osteoarthritis solidify their position on the list of degenerative disease that are amenable to treatment with anti-aging drugs.…”

“…Several common mechanisms have been proposed to drive the natural aging process and, at least, some of these mechanisms also contribute to skeletal fragility [110,111]. FoxOs are homologous to the C. elegans transcription factor DAF-16 (abnormal DAuer Formation-16).…”

Independent Roles of Estrogen Deficiency and Cellular Senescence in the Pathogenesis of Osteoporosis: Evidence in Young Adult Mice and Older Humans

“…Nevertheless, insights into the mechanisms of estrogen regulation of bone metabolism could still lead to novel drug targets for more effective prevention and treatment of osteoporosis . Moreover, because Food and Drug Administration (FDA) guidelines recommend the use of ovariectomy (OVX) as a standard preclinical animal model to demonstrate the efficacy and safety of new drugs for osteoporosis therapy, it is important to determine the extent to which this model recapitulates our expanding knowledge of the spectrum of fundamental mechanisms contributing to organismal skeletal aging . Indeed, while bone loss in humans occurs both in response to estrogen deficiency and in the setting of aging, the underlying mechanisms responsible for causing bone loss during these periods need to be understood so novel strategies can be developed to target those specific mechanisms and tailor personalized therapy to patients in a context‐specific manner.…”

“…However, the question of which specific underlying mechanism(s) drives accelerated aging in response to sex steroid deficiency remains largely unanswered. Because as in other tissues, the skeletal aging process is driven by fundamental nonadaptive mechanisms that are interconnected, linked, and overlap, we focused our primary analyses on cellular senescence biomarkers and the SASP in young adult mice that had undergone gonadectomy to avoid the confounding effects of other fundamental aging mechanisms that exist in the context of older age . In additional exploratory analyses, we measured senescence biomarkers and the SASP in human bone by taking advantage of previous study performed by our group in which bone biopsies were obtained from older postmenopausal women who received either no treatment or estrogen therapy …”

Metformin Modulates the Mechanisms of Ageing

“…Moreover, a declined activity of the immune system, termed as immunosenescence, is installed in aged people, thus impairing the clearance of senescent cells and, in turn, increasing even more the chronic inflammation state. Collectively, senescence, inflammageing and immunosenescence promote ageing and operate together, rendering aged people more susceptible to age-related diseases [87,89]. Finally, interestingly, mitochondrial dysfunction can also trigger cellular senescence, a process termed as "mitochondrial dysfunction-associated senescence" (MiDAS).…”