Persistent transcription-blocking DNA lesions trigger somatic growth attenuation associated with longevity

Abstract

Accumulation of stochastic DNA damage throughout organisms’ lifespan is thought to contribute to aging. Conversely, aging appears phenotypically reproducible and regulated through genetic pathways such as the insulin-like growth factor-1 (IGF-1) and growth hormone (GH) receptors, which are central mediators of the somatic growth axis. Here, we report that persistent DNA damage in primary cells elicits similar changes in global gene expression as those occurring in various organs of naturally aged animals. Importantly, we show that, as in aging animals, IGF-1 receptor and GH receptor expression is attenuated resulting in cellular IGF-1 resistance. This cell-autonomous attenuation is specifically induced by persistent lesions leading to RNA polymerase II stalling, in proliferating, quiescent and terminally differentiated cells, is exacerbated and prolonged in cells from progeroid mice and confers resistance to oxidative stress. Our findings suggest that DNA damage accumulation in transcribed genes in most if not all tissues, contributes to the aging-associated shift from growth to somatic maintenance that triggers stress resistance and is thought to promote longevity.

Insulin-like growth factor 1 treatment extends longevity in a mouse model of human premature aging by restoring somatotroph axis function

“…These features common to both longlived and premature-aged individuals have been proposed to arise from a progressive and age-dependent accumulation of DNA damage, which is highly exacerbated in progeroid syndromes (46). In addition, DNA damage induction in vivo has been shown to lead to a series of alterations similar to those observed in both progeroid and long-lived animals (14,44). Thus, it seems reasonable that long-lived organisms that have been able to overcome cancer, cardiovascular, or other lifethreatening pathologies accumulate DNA damage with aging that eventually elicits an adaptive stress response similar to that observed at an early age in progeroid individuals.…”

“…All these alterations seem to be part of an adaptive stress response aimed at preserving organism viability under compromising circumstances (14,15). These features common to both longlived and premature-aged individuals have been proposed to arise from a progressive and age-dependent accumulation of DNA damage, which is highly exacerbated in progeroid syndromes (46).…”

“…Paradoxically, studies have shown that reduced somatotroph signaling is a common feature of both long-lived model organisms and progeroid mice harboring alterations in DNA-repair mechanisms (14,15). However, to date no studies have been undertaken to evaluate whether the down-regulation of IGF-1 signaling observed in premature aging is a beneficial adaptive response or a detrimental event that directly contributes to the development of progeroid features.…”

Active transcriptomic and proteomic reprogramming in theC. elegansnucleotide excision repair mutant xpa-1

“…Instead the damage may persist and cause constitutive problems e.g., with transcription. 9 The existence of accelerated aging syndromes caused by DNA repair defects supports the general idea that persistent DNA damage promotes aging and age-related pathology. Studies of syndromes caused by defects in Nucleotide Excision Repair (NER), a pathway that deals with DNA damage induced by UV-light and other lesions that induce structural distortions in the DNA helix, have been highly influential (Fig.…”

“…They show a characteristic gene expression pattern with suppression of the insulin-like signaling (ILS) and activation of oxidative stress response pathways. [43][44][45][46] The transcriptomic modulation in segmental progeroid NER mutants is believed to reflect a "survival response" 47,48 since suppression of ILS through caloric restriction is associated with lifespan extension. 49,50 Similarly, characterizing the transcriptomic signatures of C. elegans xpa-1 mutants has proved to be highly informative toward understanding how normal-or near-normal-phenotypes are maintained in the absence of effective DNA repair.…”