Fig. 2 |. The threshold theory of senescent cell accumulation.

This theory postulates that once senescent cell burden exceeds a threshold, self-amplifying paracrine and endocrine spread of senescence through the SASP outpaces clearance of senescent cells by the immune system^34,219. Additionally, increased abundance of SASP factors may impede immune system function^62,78, further amplifying accumulation of senescent cells. Senescent cell accumulation may also accelerate other fundamental aging mechanisms. In studies of effects of transplanting senescent versus non-senescent cells into middle-aged mice, a minimum number of transplanted senescent cells was necessary to cause accelerated aging-like phenotypes²⁴. In conditions in which senescent cell burden is already high, such as obesity, fewer senescent cells need to be transplanted to induce the same effect as in lean mice of the same age^23,24,151. Consistent with this, in human childhood cancer survivors who have had DNA-damaging anticancer therapy, a subsequent accelerated aging-like phenotype can occur at a considerably earlier age than in older individuals who do not have a history of childhood cancer treatment¹⁶⁹. Hence, senescent cells with a proapoptotic, inflammatory SASP may need to exceed a threshold to exert detrimental effects. Systemic clearance of senescent cells by genetic or pharmacologic means tends to attenuate the other pillars of aging and can delay, prevent or alleviate multiple age-related disorders and diseases^23,24,30,49.