DNA repair mutants often show a dramatic accelerated aging phenotype, with affected animals developing signs of frailty (wrinkling, graying, osteoporosis, heart disease, senility, you name it) much more rapidly than their wildtype cohorts. In some cases, these mutants age (“segmentally,” which is to say, not in every part of the body equally) at a rate ten or twenty times faster than normal.
In contrast, small body size due to genetic dwarfism and calorie restriction (CR) are both known to extend lifespan in many organisms (at least when they’re safe and warm in the lab, and in some species possibly only when they’re inbred).
One would therefore expect that animals with DNA repair-related progeroid syndromes would be dissimilar in every regard from dwarf and CR animals — but I wouldn’t have set it up this way if that expectation weren’t wrong. Recent results from a multi-lab collaboration suggest that both certain kinds of (life-shortening) DNA repair deficiencies trigger the same alterations in metabolism that are activated during (life-prolonging) CR. From van de Ven et al.:
… Contrary to expectations, neither accelerated senescence nor acute oxidative stress hypersensitivity was detected in primary fibroblast or erythroblast cultures from multiple progeroid mouse models for defects in the nucleotide excision DNA repair pathway, which share premature aging features including postnatal growth retardation, cerebellar ataxia, and death before weaning. Instead, we report a prominent phenotypic overlap with long-lived dwarfism and calorie restriction during postnatal development (2 wk of age), including reduced size, reduced body temperature, hypoglycemia, and perturbation of the growth hormone/insulin-like growth factor 1 neuroendocrine axis. These symptoms were also present at 2 wk of age in a novel progeroid nucleotide excision repair-deficient mouse model (XPDG602D/R722W/XPA−/−) that survived weaning with high penetrance. However, despite persistent cachectic dwarfism, blood glucose and serum insulin-like growth factor 1 levels returned to normal by 10 wk, with hypoglycemia reappearing near premature death at 5 mo of age. These data strongly suggest changes in energy metabolism as part of an adaptive response during the stressful period of postnatal growth. … Specific (but not all) types of genome instability may thus engage a conserved response to stress that evolved to cope with environmental pressures such as food shortage.
So it would seem that both calorie-restricted and DNA-repair-deficient animals converge on some of the same physiological strategies, albeit with drastically different eventual results. How best to rationalize this?
Short-lived repair mutants seem to divert resources away from growth and into maintenance and repair — because they need more repair. Long-lived dwarf mutants and CR animals divert resources away from growth and into maintenance and repair — because they don’t necessarily have (or don’t believe they have) enough food to rapidly mature to adulthood. In both cases, we can understand the change in priorities as an attempt to wait out temporarily adverse conditions, waiting for things to change for the better so that the process of maturing to adulthood and sexual maturity can begin again. The DNA repair mutants, sadly, don’t know that there’s nothing temporary about their adversity: because the repair machinery itself has been compromised, no improvement will result no matter how many resources they throw at the problem — so even though they might be on the same track as the CR animals, they’ll never make it to the desired destination.
As is often the case with new data, mysteries abound: The DNA repair mutants that seemed to turn on the CR-related metabolic changes were all deficient in nucleotide excision repair (NER). A mutant in a different pathway, double-strand break repair (DSBR) showed signs of premature aging but no indication of the alterations in growth hormone release that was seen in the NER mutants. The rationalization is therefore not simply that the animals need more repair in general. Wild speculation: perhaps NER mutant cells are more prone to apoptosis, requiring active regeneration of lost cells, whereas DSBR mutations allow cells to persist, albeit in a senescent form?