Proteostasis and ageing: insights from long‐lived mutant mice. (2nd August 2017)

• Record Type: Journal Article
• Authors: Sands, William A.; Page, Melissa M.; Selman, Colin
• Is Part Of: Journal of physiology. Volume 595:Number 20(2017)
• Page Start: 6383
• Page End: 6390
• Publication Date: 2017-08-02
• Subjects: ageing -- endoplasmin reticulum stress -- immunoproteasome -- longevity -- proteasome -- proteostasis -- unfolded protein response; Physiology -- Periodicals; 612.005
• DOI: 10.1113/JP274334
• Languages: English
• ISSNs: 0022-3751

Abstract

Abstract : Primary cellular proteostatic mechanisms within mice. Multiple components of the proteostatic network are known to be deleteriously affected by ageing but such age‐associated changes may be slowed and/or delayed in long‐lived mice. Consequently, it has been suggested that the ability to better maintain proteostasis over the life‐course underlies both the greater lifespan and healthspan of long‐lived mutant mice. UPR ER, endoplasmic reticulum stress unfolded protein response; UPR mt, mitochondrial unfolded protein response; ERAD, endoplasmic reticulum associated protein degradation. Abstract: The global increase in life expectancy is creating significant medical, social and economic challenges to current and future generations. Consequently, there is a need to identify the fundamental mechanisms underlying the ageing process. This knowledge should help develop realistic interventions capable of combatting age‐related disease, and thus improving late‐life health and vitality. While several mechanisms have been proposed as conserved lifespan determinants, the loss of proteostasis – where proteostasis is defined here as the maintenance of the proteome – appears highly relevant to both ageing and disease. Several studies have shown that multiple proteostatic mechanisms, including the endoplasmic reticulum (ER)‐induced unfolded protein response (UPR), the ubiquitin–proteasome system (UPS) and autophagy, appear indispensable for longevity in many long‐lived invertebrate mutants. Similarly, interspecific comparisons suggest that proteostasis may be an important lifespan determinant in vertebrates. Over the last 20 years a number of long‐lived mouse mutants have been described, many of which carry single‐gene mutations within the growth‐hormone, insulin/IGF‐1 or mTOR signalling pathways. However, we still do not know how these mutations act mechanistically to increase lifespan and healthspan, and accordingly whether mechanistic commonality occurs between different mutants. Recent evidence supports the premise that the successful maintenance of the proteome during ageing may be linked to the increased lifespan and healthspan of long‐lived mouse mutants.