Early Chronological Aging in Human Adipose-Derived Stem Cells Marked by Distinct Transcriptional Regulation Compared to Differentiated Cells

Aging is a complex process characterized by a progressive decline in physiological integrity that leads to impaired cellular and tissue function. Adult stem cells play a critical role in organismal health and aging. Their age-related deterioration contributes to a reduced homeostatic and regenerative capacity. Notably, most studies of stem cell aging focus on the mechanisms of replicative aging in stem cells with high cellular turnover. Yet, the therapeutic potential of stem cells with low cellular turnover, such as adipose-derived stem cells (ASC), is increasingly recognized as potentially superior. The mechanism of aging in low turnover stem cells is thought to differ from those with high turnover and to more closely reflect chronological aging. The latter, however, is exceedingly difficult to study in slowly replicating primary human stem cells and thus remains poorly understood. Here, we employ our unique model of chronological aging in primary human ASCs to examine genome-wide transcriptional networks in early chronological aging using RNA-seq analyses. Our findings demonstrate that the transcriptome of aging ASCs is more stable than that of age-matched fibroblasts. Limited transcriptional modifications in aging ASCs reveal more active transcriptional profiles of cell cycle genes and translation initiation genes when compared with aging differentiated cells. Accordingly, nascent protein synthesis, measured by incorporation of op-puromycin, is increased in ASCs from older individuals, concurrent with a decreased phosphorylation at ser-51 of eIF2, a mechanism of inhibiting translation initiation. A shortened G1 phase observed in the old ASCs could be linked to the increased protein synthesis activity, potentially resulting in more active cell proliferation. This effect, however, is not detected in aging fibroblasts. The altered regulation of cell cycle in aging ASCs could allow a more active cell proliferation to meet an increase demand to preserve tissue and organ functions. These observations are consistent with data supporting the maintenance of ASC integrity in aging human adipose tissue and reveal early chronological aging mechanisms in ASCs that are inherently different from other cell types. Overall design: Examination of the transcriptome with RNA-seq in stem cells and fibroblasts

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Shan X, Roberts C, Kim EJ, Brenner A, Grant G, Percec I