Spreading Senescent Cells' Burden and Emerging Therapeutic Targets for Frailty

Abstract

The spreading of senescent cells' burden holds profound implications for frailty, prompting the exploration of novel therapeutic targets. In this perspective review, we delve into the intricate mechanisms underlying senescent cell spreading, its implications for frailty, and its therapeutic development. We have focused our attention on the emerging age-related biological factors, such as microbiome and virome alterations, elucidating their significant contribution to the loss of control over the accumulation rate of senescent cells, particularly affecting key frailty domains, the musculoskeletal system and cerebral functions. We believe that gaining an understanding of these mechanisms could not only aid in elucidating the involvement of cellular senescence in frailty but also offer diverse therapeutic possibilities, potentially advancing the future development of tailored interventions for these highly diverse patients.

Keywords: aging; cellular senescence; frailty; immunosenescence; microbiome; virome.

Figure 1

Relationship between stressors and accumulation of senescent cells resulting from failure of senescence immunosurveillance and changes in the microbiome/virome. The image is adapted and redrawn from Fried et al., 2021 [24] and Xue et al., 2019 [25].

Figure 2

Overview of mechanisms that can contribute to the rapid spreading of senescent cells in aging. Damage (e.g., replicative, oxidative, and oncogenic), impaired immunosurveillance, and persistent SASP secretion synergistically increase senescent cells’ burden in organs and tissues. Disease or other forms of stress (such as diet, environmental factors, or aging) can induce structural and functional changes in the microbiota that, in turn, can directly affect tissues or the immune system’s ability to respond to stress, such as causing systemic inflammatory aggravation. Combined therapies targeting senescent cells at different levels, such as senolytics (downstream action) and modulators of the microbiome/virome (upstream action), could display synergic beneficial effects in the therapeutic and preventive approaches for frailty.