SUMMARY Cellular senescence permanently arrests cell proliferation, often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). Loss of mitochondrial function can drive age-related declines in the function of many post-mitotic tissues, but little is known about how mitochondrial dysfunction affects mitotic tissues. We show here that several manipulations that compromise mitochondrial function in proliferating human cells induce a senescence growth arrest with a modified SASP that lacks the IL-1-dependent inflammatory arm. Cells that underwent mitochondrial dysfunction-associated senescence (MiDAS) had lower NAD+/NADH ratios, which caused both the growth arrest and prevented the IL-1-associated SASP through AMPK-mediated p53 activation. Progeroid mice that rapidly accrue mtDNA mutations accumulated senescent cells with a MiDAS SASP in vivo, which suppressed adipogenesis and stimulated keratinocyte differentiation in cell culture. Our data identify a distinct senescence response and provide a mechanism by which mitochondrial dysfunction can drive aging phenotypes.

Highlights There is no single biomarker which can robustly identify senescent cells. Widely used senescent cell biomarkers should be used in combination for accuracy. Technologies like tangential flow filtration can be used to isolate senescent cells. Other methods, like senolytic viruses, could be used to remove senescent cells. AbstractAging is the main risk factor for many degenerative diseases and declining health. Senescent To better understand cell aging and to reap the benefits of senescent cell removal, it is necessary to have a reliable biomarker to identify these cells. Following an introduction to cellular senescence, we discuss several classes of biomarkers in the context of their utility in identifying and/or removing senescent cells from tissues. Although senescence can be induced by a variety of stimuli, senescent cells share some characteristics that enable their identification both in vitro and in vivo. Nevertheless, it may prove difficult to identify a single biomarker capable of distinguishing senescence in all cell types. Therefore, this will not be a comprehensive review of all senescence biomarkers but rather an outlook on technologies and markers that are most suitable to identify and isolate senescent cells.

SummarySingle-cell-level experimentation can elucidate key biological insights about cellular aging that are masked in population-level studies. However, the extensive time requirement of tracking single cells has historically prevented their long-term longitudinal observation. Using a microfluidic device that automates microscopic monitoring of diploid Saccharomyces cerevisiae cells throughout their replicative lifespan, here we report the fundamental characteristics of single-cell aging for diploid yeast. We find that proteins with short versus long half-lives exhibit distinct dynamics as cells age and that the intercellular gene expression noise increases during aging, whereas the intracellular noise stays unchanged. A stochastic model provides quantitative mechanistic insights into the observed noise dynamics and sheds light on the age-dependent intracellular noise differences between diploid and haploid yeast. Our work elucidates how a set of canonical phenotypes dynamically change while the host cells are aging in real time, providing essential insights for a comprehensive understanding on and control of lifespan at the single-cell level.