p53 maintains healthy aging [P53KO_PTENKO_RNAseq]

The tumor suppressor p53 is a master regulator of cellar stress responses implicated in the aging process. As a tumor suppressor, the antagonistic pleiotropy (AP) theory predicts a beneficial cancer suppression function for p53 early in life that becomes detrimental late in life, for example by promoting accumulation of senescent cells, an inflammatory cell fate driven by tumor suppressors and linked to age-associated disease. Although p53 signaling is generally activated in aging and disease, p53 is also known to suppress some phenotypes of cellular senescence, and the function of p53 in aged tissues, as well as its causal role in aging, is not well-defined. Here we show, contrary to the prediction of AP, that p53 promotes healthy aging in mice by suppressing inflammation and maintaining metabolic function. Multimodal RNA, protein, epigenetic, and spatial profiling at the single-cell level in aged mouse liver confirmed the expected age-dependent increase of immune infiltration, accumulation of senescent cells, and p53 pathway activation. Knockout of p53 in vivo in hepatocytes of aged, but not young, mice further increased inflammation and immune infiltration. Mechanistically, p53 suppressed DNA replication stress and damage, a precursor to inflammatory signaling, in senescent cells and in aged liver. In aged hepatocytes, p53 directly targeted and maintained expression of metabolic genes, and knockout of p53 sensitized aged mice to metabolic stress-induced liver damage. Conversely, pharmacological activation of p53 with a small molecule MDM2 inhibitor in aged mice reversed age-associated suppression of metabolic genes, decreased age-associated inflammation, delayed onset of frailty, (and extended lifespan) of aged mice. These data suggest that in mice, p53 delays phenotypes of aging, and that this function is targetable, potentially for the benefit of healthy aging in humans.