Cellular senescence and frailty: a comprehensive insight into the causal links

Abstract

Senescent cells may have a prominent role in driving inflammation and frailty. The impact of cellular senescence on frailty varies depending on the assessment tool used, as it is influenced by the criteria or items predominantly affected by senescent cells and the varying weights assigned to these items across different health domains. To address this challenge, we undertook a thorough review of all available studies involving gain- or loss-of-function experiments as well as interventions targeting senescent cells, focusing our attention on those studies that examined outcomes based on the individual frailty phenotype criteria or specific items used to calculate two humans (35 and 70 items) and one mouse (31 items) frailty indexes. Based on the calculation of a simple "evidence score," we found that the burden of senescent cells related to musculoskeletal and cerebral health has the strongest causal link to frailty. We deem that insight into these mechanisms may not only contribute to clarifying the role of cellular senescence in frailty but could additionally provide multiple therapeutic opportunities to help the future development of a desirable personalized therapy in these extremely heterogeneous patients.

Keywords: Aging; Brain function; Cellular senescence; Frailty; Musculoskeletal health.

Fig. 1

Number of items attributed to different frailty domains in the human (70 and 35 items) and mouse (31 items) frailty index

Fig. 2

Current evidence of a causal relationship between cellular senescence and physical frailty phenotype criteria. The evidence scores are computed as no. of studies supporting a detrimental role of senescence − no. of studies supporting a beneficial role of senescence. a Evidence score computed on the basis of the results of the studies on animal models reported in Table 2. b Evidence score computed on the basis of the results of the studies with senolytic interventions reported in Table 4

Fig. 3

Current evidence of a causal relationship between cellular senescence and clinical frailty criteria. The evidence scores are computed as [(no. of studies supporting a detrimental role of senescence) − (no. of studies supporting a beneficial role of senescence)] × (no. of items assigned to the criteria in the respective FI instrument). a–c Evidence scores computed for each FI based on the results of the studies in animal models reported in Table 3. d–f Evidence score computed for each FI on the basis of the results of the studies with senolytic interventions reported in Table 5

Fig. 4

Relationship between stressors, senescent cell burden, and time to recover the physiological integrity in the face of stressors. In normal (robust) conditions, stressors may induce a transient raise of senescent cells, which likely exerts a beneficial role, and the physiological system integrity is rapidly recovered. When frailty occurs, the physiological system’s integrity cannot be recovered, and the accumulation rate of senescent cells is out of control. Given the substantial weight assigned to musculoskeletal and cerebral function-related items or criteria in various frailty assessment tools, coupled with evidence indicating the detrimental impact of accumulating senescent cells on these health domains, targeting factors that regulate the accumulation rate of senescent cells affecting musculoskeletal and cerebral function may represent a key therapeutic strategy