A Cellular Senescence-Centric Integrated Approach to Understanding Organismal Aging

Abstract

Aging remains the fundamental cause of the increased rate of morbidity and mortality in the elderly. Despite continuing research, an integrative and holistic understanding of the molecular mechanisms and effects of aging is still elusive. This presents a major challenge in biogerontology, and therefore novel strategies aimed at integrating the multifaceted nature of aging for the identification and development of successful therapeutic targets are highly desirable. At present, cellular senescence, immunosenescence, and gut microbiota dysbiosis are key known modulators of aging. However, a cellular senescence-centric integrative view that relates to the seemingly distinct processes of immunosenescence and gut microbiota dysbiosis can be envisaged which implies a more inclusive and targetable understanding of aging. The present manuscript discusses the emerging evidence and significance of cellular senescence vis-à-vis immunosenescence and gut microbiota dysbiosis in the development of potential anti-aging therapies. Underlying interconnections and mechanisms amongst these individual modulators have been deliberated to present a more coherent and tangible understanding of biological aging. It is emphasized that aging be studied within the integrative purview of these processes that may ultimately help devise a new inclusive and consolidated theory of aging with well-defined therapeutic targets.

Reversal of cellular senescence and insulin resistance in Skeletal muscle cells, via p38 mitogen-activated protein kinase inhibition

“…Circulating proteins commonly associated with SASP include, TNF-α, IL-6, IL-8, MMP, MCP-1 and IGFbinding proteins to name a few [20]. Existing work has identi ed several signal transduction pathways activated by pro-in ammatory cytokines associated with the obese phenotype but are common to the SASP and can impede insulin receptor signalling in skeletal muscle, liver, and adipose cells [21]. A majority of these complex and interrelated pathways appear to converge at the level of insulin receptor substrate 1 [22,23].…”

Exploring the emerging bidirectional association between inflamm‐aging and cellular senescence in organismal aging and disease

“…Although no single theory is yet accepted to explain the intricate processes and effects of aging, the accumulation of senescent cells appears to be strongly associated with various aging hallmarks due to the ability of these cells to both carry and induce macromolecular damage and cellular dysfunctions. 7,95 In particular, the paracrine effects of the SASP explain the widespread pathology and chronic pro-inflammatory physiological environment observed during aging.…”

“…Of the several identified hallmarks of aging, cellular senescence is gradually emerging as a dominant player and orchestrator of the various facets of aging physiology including age‐dependent diseases. It is thus not surprising that cellular senescence‐mediated mechanisms and therapeutics of aging are rapidly gaining traction 4–7 . In fact, suppression of the age‐dependent accumulation of senescent cells in several tissues and organs is increasingly being rationalized as a single modifiable target not only for improving lifespan but also several chronic diseases, including cancer and diabetes, thereby improving the healthspan 8–10 .…”