A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis

Abstract

XPF-ERCC1 endonuclease is required for repair of helix-distorting DNA lesions and cytotoxic DNA interstrand crosslinks. Mild mutations in XPF cause the cancer-prone syndrome xeroderma pigmentosum. A patient presented with a severe XPF mutation leading to profound crosslink sensitivity and dramatic progeroid symptoms. It is not known how unrepaired DNA damage accelerates ageing or its relevance to natural ageing. Here we show a highly significant correlation between the liver transcriptome of old mice and a mouse model of this progeroid syndrome. Expression data from XPF-ERCC1-deficient mice indicate increased cell death and anti-oxidant defences, a shift towards anabolism and reduced growth hormone/insulin-like growth factor 1 (IGF1) signalling, a known regulator of lifespan. Similar changes are seen in wild-type mice in response to chronic genotoxic stress, caloric restriction, or with ageing. We conclude that unrepaired cytotoxic DNA damage induces a highly conserved metabolic response mediated by the IGF1/insulin pathway, which re-allocates resources from growth to somatic preservation and life extension. This highlights a causal contribution of DNA damage to ageing and demonstrates that ageing and end-of-life fitness are determined both by stochastic damage, which is the cause of functional decline, and genetics, which determines the rates of damage accumulation and decline.

Signaling mechanisms involved in the response to genotoxic stress and regulating lifespan

“…If the damage is catastrophic, then pro-apoptotic mechanisms are activated, resulting in cell death. At the organismal level, chronic genotoxic stress causes systemic dampening of growth signals (Niedernhofer et al, 2006), affording another layer of protection. Many of the key regulators of the signaling pathways affected by genotoxins when similarly affected via genetics or pharmaceuticals extend the lifespan of cells or organisms.…”

“…IGF-1 protects cells against apoptosis in response to genotoxic stress. Seemingly in contradiction to this, in vivo chronic genotoxic stress causes a systemic reduction in circulating IGF-1 (Niedernhofer et al, 2006). This may be mediated by p53, which inhibits expression of IGF-1R and IGF-II while increasing the expression of IGFBP-3 (an IGF-1 binding protein that retains IGF-1 in the serum), all of which dampen IGF-1 signaling (Butt et al, 1999).…”

“…This endocrine response appears to be a highly conserved mechanism aimed at conserving energy resources for maintenance and repair rather than utilizing them for proliferation, and growth and was likely evolved to cope with stress (nutritional or genotoxic). As a consequence of suppressed GH-IGF-1, oxidative metabolism is decreased, while anti-oxidant defenses and DNA repair are increased (Kenyon, 2005;Niedernhofer et al, 2006). Suppression of GH-IGF-1 signaling in response to genotoxic stress therefore affords protection, minimizing further damage, including DNA damage.…”

Recruitment and positioning determine the specific role of the XPF ‐ ERCC 1 endonuclease in interstrand crosslink repair

“…An extreme progeroid syndrome was caused by a mutation in the helicase‐like domain of XPF (R153P). This patient suffered from neurological and hematological defects and a cellular sensitivity to UV and ICLs indicating both NER and ICL repair were defective (Niedernhofer et al , 2006). Another patient, with a mutation in the same XPF domain (C236R), presented with phenotypes of XP, but also of CS, such as developmental and neurological abnormalities (Kashiyama et al , 2013).…”

Modeling Alzheimer’s disease in progeria mice. An age-related concept

“…In fact, murine progeria models may mimic human aging to a greater extent than aged wild-type (WT) mice [6,]. Ercc1 −/Δ mice that model XFE progeroid syndrome develop conditions common in elderly humans such as osteoporosis, pulmonary fibrosis, chronic kidney disease, cardiovascular disease, muscle wasting, peripheral neuropathy, hepatic fibrosis, urinary incontinence, intervertebral disc degeneration, cognitive decline, and loss of hearing and vision [6,9–13]. In addition, multiple therapeutic interventions have been demonstrated to extend the health span of Ercc1 −/Δ mice [14,15], including anti-geronic therapeutics and senolytics [16,17].…”