Is cellular senescence an example of antagonistic pleiotropy?

Abstract

SummaryIt is generally accepted that the permanent arrest of cell division known as cellular senescence contributes to aging by an antagonistic pleiotropy mechanism: cellular senescence would act beneficially early in life by suppressing cancer, but detrimentally later on by causing frailty and, paradoxically, cancer. In this review, we show that there is room to rethink this common view. We propose a critical appraisal of the arguments commonly brought in support of it, and we qualitatively analyse published results that are of relevance to understand whether or not cellular senescence-associated genes really act in an antagonistic-pleiotropic manner in humans.

Irreparable telomeric DNA damage and persistent DDR signalling as a shared causative mechanism of cellular senescence and ageing

“…This proliferative arrest is called oncogene-induced senescence (OIS) and, depending on cell type and oncogene expression levels, is caused by activation of a number of diverse pathways [46]. Thus, by preventing cancer onset, in addition to causing impairment of regenerative capacity during ageing, cellular senescence has been considered as an example of antagonistic pleiotropy, although this has recently put to question [47]. In some human cells, oncogene expression initially causes cells to hyper-proliferate, which leads to aberrantly increased DNA replication rates causing frequent DNA replication fork stalling events.…”

Cellular senescence in aging and age-related disease: from mechanisms to therapy

“…The antagonistic pleiotropy theory of aging proposes that organismal fitness declines, at least in part, because natural selection favors genetic programs that have beneficial effects on reproductive fitness early in life without regard for negative impacts on health at later, post-reproductive ages 2 . One set of genes that is likely to qualify as antagonistically pleiotropic is the regulators of cellular senescence 3 , a potent anticancer mechanism that prevents malignancies by permanently withdrawing (pre-) neoplastic cells from the cell cycle 4,5 but also has been implicated as a driver of aging and age-related disease 6–8 .…”

Senescence at a glance

“…This is in line with the finding that cellular senescence is associated with age-related phenotypes and the removal of senescent cells is able to prevent or delay tissue dysfunction and extend healthspan (Baker et al, 2011). Nonetheless, the notion of senescence as an example of antagonistic pleiotropy has also been challenged recently because there is little evidence that the positive effects of senescence on survival predominate at young ages and the negative effects predominate at late ages (Giaimo and d'Adda di Fagagna, 2012).…”