Brd2 haploinsufficiency extends lifespan and healthspan in C57B6/J mice.

Shilpa Pathak,Mark E Hester,David A Greenberg,William C L Stewart,Christin E Burd,Christoph Englert

doi:10.1371/journal.pone.0234910

Abstract

Aging in mammals is the gradual decline of an organism's physical, mental, and physiological capacity. Aging leads to increased risk for disease and eventually to death. Here, we show that Brd2 haploinsufficiency (Brd2+/-) extends lifespan and increases healthspan in C57B6/J mice. In Brd2+/- mice, longevity is increased by 23% (p<0.0001), and, relative to wildtype animals (Brd2+/+), cancer incidence is reduced by 43% (p<0.001). 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.

Highlights

Inherent in the aging process is a gradual decline in physical, cognitive, and physiological capacity, an increasing risk of disease, and death
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 [1,2,3] 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 [4, 5], we found that HETs, which are overtly normal [1, 3], have significantly longer lifespans and show healthier-aging phenotypes, including reduced cancer incidence and improved kidney function, as compared to wildtype mice

Summary

Introduction

Inherent in the aging process is a gradual decline in physical, cognitive, and physiological capacity, an increasing risk of disease, and death. 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 [1,2,3] 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 [4, 5], we found that HETs, which are overtly normal [1, 3], have significantly longer lifespans and show healthier-aging phenotypes, including reduced cancer incidence and improved kidney function, as compared to wildtype mice.

Methods

Results

Conclusion