Contesting the dogma of an age-related heat shock response impairment: implications for cardiac-specific age-related disorders

Abstract

Ageing is associated with the reduced performance of physiological processes and has been proposed as a major risk factor for disease. An age-related decline in stress response pathways has been widely documented in lower organisms. In particular, the heat shock response (HSR) becomes severely compromised with age in Caenorhabditis elegans. However, a comprehensive analysis of the consequences of ageing on the HSR in higher organisms has not been documented. We used both HS and inhibition of HSP90 to induce the HSR in wild-type mice at 3 and 22 months of age to investigate the extent to which different brain regions, and peripheral tissues can sustain HSF1 activity and HS protein (HSP) expression with age. Using chromatin immunoprecipitation, quantitative reverse transcription polymerase chain reaction, western blotting and enzyme linked immunosorbent assay (ELISA), we were unable to detect a difference in the level or kinetics of HSP expression between young and old mice in all brain regions. In contrast, we did observe an age-related reduction in chaperone levels and HSR-related proteins in the heart. This could result in a decrease in the protein folding capacity of old hearts with implications for age-related cardiac disorders.

The Biology of Proteostasis in Aging and Disease

“…This observation has led to the hypothesis that the pathways necessary to maintain proteostasis and suppress protein misfolding and aggregation are progressively compromised with age, eventually leading to disease onset. In support of this idea, reduced expression of molecular chaperones, altered proteasome activity, and disruption of stress responses have been observed in aged rodent tissues and senescent human cells (36, 111, 112). Additionally, an investigation of chaperone and cochaperone gene expression in young (36±4 years of age) and aged (73 ±4 years of age) human brain tissue revealed that of 332 genes examined, 101 are significantly repressed with age, including HSP70, HSP40, HSP90, and TRiC genes (113).…”

Modulation of Heat Shock Factor 1 Activity through Silencing of Ser303/Ser307 Phosphorylation Supports a Metabolic Program Leading to Age-Related Obesity and Insulin Resistance

“…Regulation of HSF1 and downstream target genes in tissues of HSF1 303A/307A mice during chronological aging under basal conditions or upon exposure to heat-induced stress. An age-related decline in stress response and HSF1 activity has been documented (8,34), but the underlying mechanism remains elusive. Histological sections of organs (cardiac and skeletal muscles, liver, kidney, and brain) from young and aged mice, stained for hematoxylin and eosin (H&E), did not reveal apparent morphological changes (Fig.…”

Transthyretin Suppresses Amyloid-β Secretion by Interfering with Processing of the Amyloid-β Protein Precursor

“…It is known that the concentration of TTR in the serum of humans and mice decreases with aging but there are no data available documenting an alteration in neuronal TTR production with increasing age [54,55]. It has previously been suggested that neuronal HSF1 responses, primarily measured in terms of HSP70, are reduced in aged mice but recent data suggest that may not be the case [56,57]. If neuronal TTR production is diminished in aging, whether it reflects reduced HSF1 responsiveness or not, its reduction could contribute to the association of sporadic neurodegenerative disease with age.…”