There are innumerable studies showing small gains in mouse life span. Most cannot be reproduced, particularly the older ones, those that took place before it was common knowledge in the research community that one has to very aggressively control for accidental calorie restriction. If an intervention makes mice eat less, then they will tend to live longer, even if the intervention is modestly toxic. The improvements to health and longevity produced by calorie restriction in short-lived species are larger than near all other interventions assessed to date.
Nonetheless, mechanisms that reliably (and usually modestly) slow aging in short-lived species do exist, acting to adjust metabolism into a more favorable state. Many are connected to calorie restriction, in which stress response processes are upregulated, and are as a consequence fairly well studied. Numerous interventions exist to manipulate these mechanisms, but it is not expected that sizable results in mice will translate to sizable results in humans, at least not for this class of approach. The benefit to longevity is observed to scale down as species life span increases. This may be because famine is seasonal, and thus evolutionary adaptation that allows passage through famine to reproduce on the other side must produce proportionally larger gains in life span in short-lived species than in long-lived species.
Interestingly, the intervention described in today’s open access paper was an accidental discovery by researchers working outside the field of aging research. A gene related to epilepsy, Brd2, turned out to be connected to a number of longevity-associated cellular processes. Inhibition of Brd2 extends mouse life span by a large enough amount to suggest that it is a real effect, though by much less than is achieved via calorie restriction.
Although it is thought that aging results from the cumulative effects of molecular and cellular damage, we serendipitously discovered that a Brd2-haploinsufficient (Brd2+/-; denoted HET) mouse model we developed to study epilepsy had a much longer lifespan compared to wild type (Brd2+/+; denoted WT) mice. In pursuing the mechanism by which BRD2, a bromodomain (BET) protein, predisposed to epilepsy, we found that HETs, which are overtly normal, not only have significantly longer lifespans but also show healthier-aging phenotypes, including reduced cancer incidence and improved kidney function, as compared to wildtype mice.
There are several genes and molecular processes that are known to influence longevity in mice. Many of those genes are in turn influenced by Brd2. For example, Brd2 haploinsufficiency downregulates IGF signaling, and IGF signaling is decreased in calorically restricted mice – a dietary intervention that increases lifespan. Similarly, Brd2 haploinsufficiency up-regulates genes in the Sirtuin pathway, and up-regulation of the Sirtuin pathway is associated with increased lifespan. Specifically, Sirtuin 1 (SIRT1) and its homologs regulate longevity-related processes such as DNA repair, genome stability, inflammation, apoptosis, cell cycle progression and mitochondrial respiration. Reduced expression of Brd2 also increases p53, Nqo1, and Hmox1 expression, all of which reduce oxidative stress. In addition, upregulation of p53 increases genomic stability, promotes DNA repair, and increases lifespan. Because Brd2 haploinsufficiency is tied to multiple longevity-related genes and molecular processes, reduced expression of Brd2 could be a fundamental – and heritable – factor influencing lifespan.
Here, we show that Brd2 haploinsufficiency (Brd2+/-) extends lifespan and increases healthspan in C57B6/J mice. In Brd2+/- mice, longevity is increased by 23%, and, relative to wildtype animals (Brd2+/+), cancer incidence is reduced by 43%. In addition, relative to age-matched wildtype mice, Brd2 heterozygotes show healthier aging including: improved grooming, extended period of fertility, and lack of age-related decline in kidney function and morphology. Our data support a role for haploinsufficiency of Brd2 in promoting healthy aging. We hypothesize that Brd2 affects aging by protecting against the accumulation of molecular and cellular damage. Given the recent advances in the development of BET inhibitors, our research provides impetus to test drugs that target BRD2 as a way to understand and treat/prevent age-related diseases.