About the Vijg lab

Life span is species-specific and determined by life history encoded by the species’ total complement of genetic information. Our research has shown that the human life span has a natural limit that fluctuates around 115 years (Dong et al., 2016). This raises two questions. First, is it possible to break through that ceiling and develop interventions to increase the maximum human life span? Over the last two decades evidence with model organisms, from yeast and worms to flies and mice, has accumulated that life span can be significantly extended by targeting conserved pathways of aging. As part of an NIH supported U19 consortium of investigators we are currently using whole-exome sequences of human centenarians to identify druggable genetic targets for increasing human healthy life span (http://u19aging.einstein.yu.edu/). 

    A second question involves the mechanism that dictates species-specific limits to life span. This is essentially the question of what causes aging and the large diversity of life spans in the animal world. We hypothesize that a major, highly conserved mechanism of aging is genome instability. To test this hypothesis, initially mouse and fly models were developed in the lab that harbor reporter genes that can be recovered in E. coli and screened for the presence of mutations inactivating or partially inactivating the reporter gene (Boerrigter et al., 1995; Dollé et al., 1997; Dollé et al., 2000; Garcia et al., 2007). Using these model organisms we conclusively demonstrated that de novo somatic mutations accumulate with age in a species- and tissue-specific manner.

    More recently, we developed single-cell methods to quantitatively analyze various types of mutations across the genome in relation to gene expression changes in the same cells (Gundry et al., 2012; Dong et al., 2017). We are specifically interested in large genome rearrangements, which could lead to aging and disease by deregulating gene expression (e.g., through position effects, haploinsufficiency or chromatin remodeling). In this respect, the lab has provided evidence for DNA double-strand breaks, a major cause of genome rearrangements, to cause multiple symptoms of aging in the mouse (White et al., 2015). Assays to specifically study these events have been developed (Quispe-Tintaya et al., 2016) and new, single-cell assays are currently under development. Increased somatic mutation loads, most notably genome rearrangements, could lead to increased transcriptional noise, i.e., random cell-to-cell variation in levels of gene expression, which we observed in cardiomyocytes of aged mice (Bahar et al., 2006). In turn, this could explain, at least in part, the nature of the aging process, which is characterized by genetic and epigenetic drift that could ultimately lead to the progressive increase in systemic malfunctioning that we call aging.

Model of how somatic DNA damage and mutations could cause aging. In the young tissue on the left somatic mutations have already begun to accumulate during development (red cells). At old age (right) DNA damage responses have led to cell loss through apoptosis and increased somatic mutation loads. Occasionally a combination of driver mutations may give rise to a neoplastic of hyperplastic lesion. This model is currently used in the lab to test if mutation loads in human tissues rise to levels that could have the deleterious effects observed at old age.

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