A mouse genetic locus with death clock and life clock features

Abstract

A senility syndrome, with weight loss and priapism, occurs in CBAT6/T6 mice, an exceptionally long-lived strain. Instead of dying at the expected time, these mice get senile weight loss and priapism and go on living. We have postulated that a mutant death clock kills the wrong neurons. Crosses with the NZW and C57BL/6 strains show causation by a single genetic locus (Priap1), with a pronounced gene dosage effect on timing. We report here that various cancers were the cause of death in 31 of 32 NZW mice, compared to only five of 22 CBAT6/T6 mice, a highly significant difference (P<0.001). The longevity of (CBAT6/T6xNZW)F1 hybrids, and the segregation of longevity with priapism and senile weight loss in (CBAT6/T6xNZW) F2 hybrids, indicates that Priap1, or a linked gene, inhibits the cancers that usually shorten the lives of NZW mice. If a timer gene is involved, the cancer resistance action could be because the locus impedes the normal mid-life regression of anti-cancer defence. The priapism suggests loss of the medullary reticular formation neurons which normally inhibit male spinal sexual reflexes. In this region of the medulla there are also the respiratory and cardiac control centres, where apoptotic neuron destruction by the wild-type locus could govern maximal life-span. The CBAT6/T6 locus may be a mutant life-stage control clock. Its discovery could be the revelation of a new, major class of aetiology of disease.