Molecular basis of mitotic decline during human aging

Abstract

Aneuploidy, an abnormal chromosome number, has been linked to aging and age-20 associated diseases, but the underlying molecular mechanisms remain unknown. Supported by 21 direct live-cell imaging of young, middle-aged and old-aged primary human dermal fibroblasts, 22 we found that aneuploidy increases with aging due to general dysfunction of the mitotic Aging has been linked to an increase in aneuploidy for the past several decades 1 . This 34 association has been well documented for oocytes and is considered to be the main cause of 35 miscarriage and birth defects in humans 2 . However, aneuploidy can also arise in somatic cells, 36 and a number of studies have reported age-dependent increases in aneuploidy [3][4][5][6][7] . These studies 37 have shown that aging is positively correlated with the incidence of chromosome mis- The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/261008 doi: bioRxiv preprint first posted online Feb. 6, 2018; and the lower mitotic indexes of elderly cell cultures has limited these studies from clearly 43 demonstrating whether mitotic genes are repressed intrinsically in old dividing cells. Moreover, 44 analysis of the mitotic process in aging models and diseases has been scarce and a 45 comprehensive analysis of cell division efficiency in naturally aged cells is largely missing. 46More recently, aneuploidy has been also linked to aging. Studies of aneuploidy-prone mouse 47 models exhibiting increased rates of chromosome mis-segregation uncovered a unanticipated 48 nexus with the rate of aging and the development of age-related pathologies [11][12][13][14] Results 72Aneuploidy increases during natural aging 73In our study we used human dermal fibroblasts (HDFs) collected from healthy Caucasian males 74 with ages ranging from neonatal to octogenarian ( Supplementary Fig.1a), to test whether The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/261008 doi: bioRxiv preprint first posted online Feb. 6, 2018; strict quantitative parameters by microscopy analysis, in the proliferating fibroblast cultures from 89 older individuals and the HGPS patient ( Supplementary Fig.1b-g), thus validating their 90 suitability as models of advanced and premature aging, respectively. 91To determine if aneuploidy increases with aging, we performed fluorescence in situ 92 hybridization (FISH) analysis for three chromosome pairs. We found significantly higher 93 aneusomy indexes in asynchronous cell populations of middle-aged, old-aged and progeria 94 samples (Fig. 1a,b). However, because aneuploid cells are most likely outcompeted in culture by 95 diploid cells 17 , thereby diluting the aneuploidy index, we additionally measured aneuploidy in a 96 post-mitotic cell subpopulation generated during a 24h treatment with the cytokinesis inhibitor 97 cytochalasin D (Fig. 1a,c). Using this approach, we observed even higher aneuploidy in the 98 middle-aged, old-aged and progeria cultures. Thus, the mild aneuploidy levels found ...

QTL mapping and BSA-seq map a major QTL for the node of the first fruiting branch in cotton

“…As reported, pan1 functions in cell asymmetric division and development (Best et al, 2021;Lu et al, 2022). Ghir_D03G012390 codes a FAM214B protein, which is vital in cell aging (Hernandez-Segura et al, 2017;Macedo et al, 2018). As JF173 has lower NFFB and better early maturity, the different expression patterns of Ghir_D03G012430 and Ghir_D03G012390 imply that they may be involved in NFFB formation and earliness regulation in cotton.…”