Final Report Summary - STEMCELLGERONTOGENES (Longevity and aging associated genes that control self-renewal and function of adult stem cells during aging)
Growing numbers of genes are associated with the development of aging associated pathologies and diseases and are referred to as “gerontogenes”. The functional role of gerontogenes in driving organism aging remains mostly unknown. The project “StemCellGerontoGenes” tested the hypothesis that gerontogenes cause organism aging by limiting the function of stem cells in adult tissues during lifetime. In the recent years it has been demonstrated that stem cells are present in almost all tissue of the adult organism. Stem cells are important for organ maintenance and regeneration throughout life, but the function of stem cells declines during aging. We hypothesized that changes in the activity of gerontogenes can accelerate the aging process of stem cells thereby accelerating organism aging.
The project identified several genetic factors that limit the functionality of stem cells in response to DNA damage during aging: The study identified several new mechanisms how stem cells react to DNA damage involving stem cell intrinsic signals as well as signals from the stem cell niche (Meena et al. EMBO J 2015, Tao et al. EMBO J 2015, Wang et al. 2014). The study result appears to be important for immune function decline during aging. In aging mice, the regulator of circadian gene expression, Per2, was shown to limit the function of hematopoietic stem and progenitor cells in maintaining lymphopoiesis (the generation of immune cells). Of note, the deletion of Per2 was sufficient to improve the maintenance of lymphopoiesis and immune functions in aging mice (Wang et al. NCB 2016). Together, these findings improve our understanding how DNA damage limits the function of stem cells and how this can contribute to disease development during aging.
In addition to cell intrinsic, molecular damages, cell extrinsic factors, such as metabolism and dietary factors, can influence organism aging. It is known that dietary restriction (DR) can delay aging in different organisms but its effect on lifespan elongation in primates is limited and not observed in all studies, suggesting that DR may also have negative effects despite improving health parameters in aging. Results from the StemCellGerontoGene project supports this assumption showing that DR can delay early aging of hematopoietic stem cells (HSCs) by suppressing Igf1-dependent growth signaling, but at the same time DR was found to impair the differentiation capacity of the stem cells by suppression of secreted cytokines that are required for differentiation, such as IL6 and IL7, which led to immune defects and an increased risk of infection (Tang et al. J Ex Med 2016).
Together, the project revealed that aging-associated accumulation of cell intrinsic damages as well as alteration in stem cell niches and the circulatory environment (such as metabolic changes) influence stem cell aging. How genes and environment interact in driving stem cell and organism aging appears to be one of the most interesting questions in the field. Our studies on muscle stem cells (MuSCs) showed that chemical modification of the stem cell DNA (so called epigenetic modification) are remodeled in response to tissue injury, when the stem cells get activated. Interestingly our study revealed that this remodeling of the epigenome in response to tissue injury/stress is disturbed during aging. Epigenetic changes in aged stem cells overshoot and this leads to an enhanced opening of the chromatin and an aberrant activation of embryonic pathways driven by the Hoxa9 gene – a master regulator building the bodyplan during the development of the embryo (Schwörer et al. Nature 2016). Based on these results we propose a two-stage model of stem cell aging, indicating that the epigenome is influenced by cell intrinsic damages and extracellular alterations that occur during aging. These alterations in the epigenome limit stem cell function (stage-1), which in turn promote the selection of altered stem cells that carry genetic mutations or epigenetic drifts (stage-2). Both processes lead to the decline in stem cell function aggravating impairments in organ maintenance and the development of diseases during aging (for review of our concept see: Ermolaeva et al. 2018).
Together, work within the project “StemCellGerontoGenes” has improved our understanding on how genes and gene/environment interactions affect stem cell and organism aging and thus provides a rational basis for the future development of therapies aiming to facilitate health aging.
The project identified several genetic factors that limit the functionality of stem cells in response to DNA damage during aging: The study identified several new mechanisms how stem cells react to DNA damage involving stem cell intrinsic signals as well as signals from the stem cell niche (Meena et al. EMBO J 2015, Tao et al. EMBO J 2015, Wang et al. 2014). The study result appears to be important for immune function decline during aging. In aging mice, the regulator of circadian gene expression, Per2, was shown to limit the function of hematopoietic stem and progenitor cells in maintaining lymphopoiesis (the generation of immune cells). Of note, the deletion of Per2 was sufficient to improve the maintenance of lymphopoiesis and immune functions in aging mice (Wang et al. NCB 2016). Together, these findings improve our understanding how DNA damage limits the function of stem cells and how this can contribute to disease development during aging.
In addition to cell intrinsic, molecular damages, cell extrinsic factors, such as metabolism and dietary factors, can influence organism aging. It is known that dietary restriction (DR) can delay aging in different organisms but its effect on lifespan elongation in primates is limited and not observed in all studies, suggesting that DR may also have negative effects despite improving health parameters in aging. Results from the StemCellGerontoGene project supports this assumption showing that DR can delay early aging of hematopoietic stem cells (HSCs) by suppressing Igf1-dependent growth signaling, but at the same time DR was found to impair the differentiation capacity of the stem cells by suppression of secreted cytokines that are required for differentiation, such as IL6 and IL7, which led to immune defects and an increased risk of infection (Tang et al. J Ex Med 2016).
Together, the project revealed that aging-associated accumulation of cell intrinsic damages as well as alteration in stem cell niches and the circulatory environment (such as metabolic changes) influence stem cell aging. How genes and environment interact in driving stem cell and organism aging appears to be one of the most interesting questions in the field. Our studies on muscle stem cells (MuSCs) showed that chemical modification of the stem cell DNA (so called epigenetic modification) are remodeled in response to tissue injury, when the stem cells get activated. Interestingly our study revealed that this remodeling of the epigenome in response to tissue injury/stress is disturbed during aging. Epigenetic changes in aged stem cells overshoot and this leads to an enhanced opening of the chromatin and an aberrant activation of embryonic pathways driven by the Hoxa9 gene – a master regulator building the bodyplan during the development of the embryo (Schwörer et al. Nature 2016). Based on these results we propose a two-stage model of stem cell aging, indicating that the epigenome is influenced by cell intrinsic damages and extracellular alterations that occur during aging. These alterations in the epigenome limit stem cell function (stage-1), which in turn promote the selection of altered stem cells that carry genetic mutations or epigenetic drifts (stage-2). Both processes lead to the decline in stem cell function aggravating impairments in organ maintenance and the development of diseases during aging (for review of our concept see: Ermolaeva et al. 2018).
Together, work within the project “StemCellGerontoGenes” has improved our understanding on how genes and gene/environment interactions affect stem cell and organism aging and thus provides a rational basis for the future development of therapies aiming to facilitate health aging.