DNA Damage Induced Cell Fates during Aging

Aging is a progressive loss of normal physiology, ultimately resulting in age-related pathology. One of the main drivers of aging is an accumulation of irreparable damage to the genome. This damage results in both an increase in cells undergoing apoptosis and an accumulation of senescent cells. These cell fates prevent oncogenesis at the expense of tissue homeostasis loss. A disproportional amount of apoptotic cells would severely damage tissue structure, while senescent cells have an altered secretion phenotype that reduces tissue function. We aimed to unravel the mechanisms and functions of age-related DNA damage responses to ultimately identify potential strategies that prolong healthspan during aging. We discovered that FOXO4 is progressively upregulated after senescence induction and is found in damage foci in senescent cells. Here, FOXO4 inhibits apoptosis through interacting with p53. We have developed a FOXO4-DRI peptide that blocks this interaction and thereby potently and selectively kills senescent cells, improving tissue homeostasis in fast aging XpdTTD/TTD and naturally aged mice. Furthermore, we have shown that this peptide can target cancer cells that exhibit senescence features, indicating that FOXO4-DRI has the potential to target the tumor micro-environment as well as the tumor itself. Besides senescence, we highlighted a micro-RNA signature that is upregulated during aging and inhibits DNA damage-dependent apoptosis in vitro. Furthermore, we showed that this signature is transferred to neighboring cells via extracellular vesicles. The miRNA targets and in vivo role were unknown and therefore we studied miR-30, a representative miRNA. MiR-30 inhibition proved to constitutively upregulate p53 expression, increasing apoptosis after UV-damage. This has potential detrimental effects during aging, since mouse models where p53 levels are increased show accelerated aging. Increasing cell preservation miRNAs may prevent apoptosis induction in cell types that are prone to cell death during aging. Overall this thesis illustrates how apoptosis and senescence underlie organismal aging and provides starting points for the development of potential therapeutic treatment for age-related pathology.

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