The genome is constantly attacked by genotoxic insults. DNA damage has long been established as a cause of cancer development through its mutagenic consequences. Conversely, radiation therapy and chemotherapy induce DNA damage to drive cells into apoptosis or senescence as outcomes of the DNA damage response (DDR). More recently, DNA damage has been recognized as a causal factor for the aging process. The role of DNA damage in aging and age-related diseases is illustrated by numerous congenital progeroid syndromes that are caused by mutations in genome maintenance pathways. During the past 2 decades, understanding how DDR drives cancer development and contributes to the aging process has progressed rapidly. It turns out that the DDR factor p53 takes center stage during tumor development and also plays an important role in the aging process. Studies in metazoan models ranging from to mammals have revealed cell-autonomous and systemic DDR mechanisms that orchestrate adaptive responses that augment maintenance of the aging organism amid gradually accumulating DNA damage.

DNA damage responses have been well characterized in their cell-autonomous checkpoint functions leading to cell cycle arrest, senescence, and apoptosis 1. In contrast, systemic responses to tissue-specific genome instability remain poorly understood. In adult C. elegans worms germ cells undergo mitotic and meiotic cell divisions while somatic tissues are entirely postmitotic. Consequently, DNA damage checkpoints function specifically in the germline 2, whereas somatic tissues in adult C. elegans are highly radio-resistant 3. Some DNA repair systems such as global-genome nucleotide excision repair (GG-NER) remove lesions specifically in germ cells 4. Here we investigated how genome instability in germ cells affects somatic tissues in C. elegans. We show that exogenous and endogenous DNA damage in germ cells evokes elevated resistance to heat and oxidative stress. The somatic stress resistance is mediated by the ERK MAP kinase MPK-1 in germ cells that triggers the induction of putative secreted peptides associated with innate immunity. The innate immune response leads to activation of the ubiquitin-proteasome system (UPS) in somatic tissues, which confers enhanced proteostasis and systemic stress resistance. We propose that elevated systemic stress resistance promotes endurance of somatic tissues to allow delay of progeny production when germ cells are genomically compromised.

Pharmacologically active compounds with preferential cytotoxic activity for senescent cells, known as senolytics, can ameliorate or even revert pathological manifestations of senescence in numerous preclinical mouse disease models, including cancer models. However, translation of senolytic therapies to human disease is hampered by their suboptimal specificity for senescent cells and important toxicities that narrow their therapeutic windows. We have previously shown that the high levels of senescence-associated lysosomal β-galactosidase (SA-β-gal) found within senescent cells can be exploited to specifically release tracers and cytotoxic cargoes from galactose-encapsulated nanoparticles within these cells. Here, we show that galacto-conjugation of the BCL-2 family inhibitor Navitoclax results in a potent senolytic prodrug (Nav-Gal), that can be preferentially activated by SA-β-gal activity in a wide range of cell types. Nav-Gal selectively induces senescent cell apoptosis and has a higher senolytic index than Navitoclax (through reduced activation in nonsenescent cells).Nav-Gal enhances the cytotoxicity of standard senescence-inducing chemotherapy (cisplatin) in human A549 lung cancer cells. Concomitant treatment with cisplatin and Nav-Gal in vivo results in the eradication of senescent lung cancer cells and significantly reduces tumour growth. Importantly, galacto-conjugation reduces Navitoclaxinduced platelet apoptosis in human and murine blood samples treated ex vivo, and thrombocytopenia at therapeutically effective concentrations in murine lung cancer models. Taken together, we provide a potentially versatile strategy for generating effective senolytic prodrugs with reduced toxicities.