Systemic DNA damage responses in aging and disease
Björn Schumacher
Institute for Genome Stability in Aging and Disease, Medical Faculty, Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD) Research Centre and Centre for Molecular Medicine (CMMC), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany
[email protected]
While somatic tissues age, germ cells indefinitely perpetuate the genetic information. According to the disposable soma theory, selective pressure has shaped maintenance and repair mechanisms that ensure somatic functioning early in life, while the soma may decay upon successful reproduction. We focus on three central questions: (1) How is somatic maintenance adapted to the requirements of the germline, (2) which processes determine somatic maintenance and thus control aging, and (3) how can germ cells be immortal? The causal contribution of DNA damage not only to cancer development but evenly to the aging process has been demonstrated by progeroid syndromes that are caused by mutations in DNA repair genes. We have established the nematode C. elegans as metazoan model to investigate the consequences of DNA repair defects that in humans cause either cancer predisposition or developmental retardation and premature aging. Using this model we identified germline DNA damage induced systemic stress resistance (GDISR) as adaptive mechanism of somatic maintenance to reproductive requirements. In response to persistent DNA damage in somatic tissues, we determined that the longevity assurance factor DAF-16 overcomes developmental growth retardation and maintains tissue functionality by elevating tolerance to DNA lesions that accumulate with aging. Using an integrated proteomics, phospoproteomics and lipidomics analysis of the in vivo response to persistent DNA lesions we revealed a shift in proteostasis towards autophagy, a dampening of glucose and lipid metabolism, and functionally implicate IIS, EGF-, and AMPK-like signalling. Our data provide new insights into the organism’s response program to DNA damage during aging and suggest new intervention targets for triggering stress responses to antagonize the detrimental consequences of genome instability.
Institute for Genome Stability in Aging and Disease, Medical Faculty, Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD) Research Centre and Centre for Molecular Medicine (CMMC), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany
[email protected]
While somatic tissues age, germ cells indefinitely perpetuate the genetic information. According to the disposable soma theory, selective pressure has shaped maintenance and repair mechanisms that ensure somatic functioning early in life, while the soma may decay upon successful reproduction. We focus on three central questions: (1) How is somatic maintenance adapted to the requirements of the germline, (2) which processes determine somatic maintenance and thus control aging, and (3) how can germ cells be immortal? The causal contribution of DNA damage not only to cancer development but evenly to the aging process has been demonstrated by progeroid syndromes that are caused by mutations in DNA repair genes. We have established the nematode C. elegans as metazoan model to investigate the consequences of DNA repair defects that in humans cause either cancer predisposition or developmental retardation and premature aging. Using this model we identified germline DNA damage induced systemic stress resistance (GDISR) as adaptive mechanism of somatic maintenance to reproductive requirements. In response to persistent DNA damage in somatic tissues, we determined that the longevity assurance factor DAF-16 overcomes developmental growth retardation and maintains tissue functionality by elevating tolerance to DNA lesions that accumulate with aging. Using an integrated proteomics, phospoproteomics and lipidomics analysis of the in vivo response to persistent DNA lesions we revealed a shift in proteostasis towards autophagy, a dampening of glucose and lipid metabolism, and functionally implicate IIS, EGF-, and AMPK-like signalling. Our data provide new insights into the organism’s response program to DNA damage during aging and suggest new intervention targets for triggering stress responses to antagonize the detrimental consequences of genome instability.
