CISD2 Affects Lifespan in Mice
Yet another new longevity-affecting gene is cataloged in this research. It may work through increased autophagy and thus more active cellular housekeeping activities:
CISD2, an evolutionarily conserved novel gene, plays a crucial role in lifespan control and human disease. Mutations in human CISD2 cause type 2 Wolfram syndrome, a rare neurodegenerative and metabolic disorder associated with a shortened lifespan. Significantly, the CISD2 gene is located within a region on human chromosome 4q where a genetic component for human longevity has been mapped through a comparative genome analysis of centenarian siblings.We created Cisd2 knockout (loss-of-function) and transgenic (gain-of-function) mice to study the role of Cisd2 in development and pathophysiology, and demonstrated that Cisd2 expression affects lifespan in mammals. In the Cisd2 knockout mice, Cisd2 deficiency shortens lifespan and drives a panel of premature aging phenotypes. Additionally, an age-dependent decrease of Cisd2 expression has been detected during normal aging in mice. Interestingly, in the Cisd2 transgenic mice, we demonstrated that a persistent level of Cisd2 expression over the different stages of life gives the mice a long-lived phenotype that is linked to an extension in healthy lifespan and a delay in age-associated diseases.
At the cellular level, Cisd2 deficiency leads to mitochondrial breakdown and dysfunction accompanied by cell death with autophagic features. Recent studies revealed that Cisd2 may function as an autophagy regulator involved in the Bcl-2 mediated regulation of autophagy. Furthermore, Cisd2 regulates Ca2+ homeostasis and Ca2+ has been proposed to have an important regulatory role in autophagy. Finally, it remains to be elucidated if and how the regulation in Ca2+ homeostasis, autophagy and lifespan are interconnected at the molecular, cellular and organism levels.
The supposed lifespan result was actually published a couple of years ago (Human Molecular Genetics 21(18):3956–3968; PMID 22661501); I see to my surprise that FA! didn't mention it at the time. Anyway, this is just another in a long series of instantiations of the Original Sin of biogerontology: short-lived controls.
Whether it's messed-up mutants that die early of things of purely putative mechanistic or structural significance to 'normal' aging, or (most commonly -- resveratrol and many others) diabetic obesity from overfeeding, or malnourishment, or failing to keep a good lid on pathogens, you raise a colony in whicih ALL the animals are short-lived, by incompetence or by design; then if your intervention helps to partially normalize their miserably short lives, you proclaim a radical life-extension breakthrough.
A normal, healthy, well-husbanded mouse with intact genetics will on av'g live ~900 days at maximum (tenth-decile survivorship) 1100 d, as is routine in the standard control groups in studies run by people who know what they're doing (Spindler, Weindruch, Miller, etc). In this study, the maximum lifespan of the female control and transgenic animals were (respectively) 900 and 1170 days. In other words, the "life extension" granted to these animals by the transgene was only to let them live as long as they should have under control conditions, with no intervention.