Extended longevity of Caenorhabditis elegans by knocking in extra copies of hsp70F, a homolog of mot‐2 (mortalin)/mthsp70/Grp75

Abstract

The Caenorhabditis elegans homolog of mortalin/mthsp70/Grp75 (called mot-2 hereafter) was isolated by screening of a nematode cDNA library with mouse mot-2 cDNA. The isolated clone matched to hsp70F of C. elegans. Analysis with two of the antibodies raised against hsp70F revealed that unlike mammalian mot-2, it is heat inducible. Transient induction of hsp70F by heat shock led to a slight (<13%) extension in the C. elegans life span. The transgenic worms that constitutively over-expressed hsp70F predominantly in muscle showed life span extension (approximately 43% for mean and approximately 45% for maximum life span) as compared to the wild-type and green fluorescent protein-transgenic worms. Life span extension of human cells was obtained by over-expression of mot-2 [Kaul et al. (2000) FEBS Lett. 474, 159-164]. Our results show, for the first time, that this member of the hsp70 family governs the longevity of worms and thus there are common pathways that determine mammalian and worm longevity.

The Life Span Determinant p66Shc Localizes to Mitochondria Where It Associates with Mitochondrial Heat Shock Protein 70 and Regulates Trans-membrane Potential

“…Treatment with H 2 O 2 induces up-regulation of mtHsp70, which is thought to protect mitochondria from oxidative stress (25). Depletion of mtHsp70 sensitizes cells to ionizing radiations, whereas its over-expression inhibits apoptosis and delays the senescence of primary cells (22,26,27). It appears, therefore, that mtHsp70 acts in the mitochondria to prevent oxidative stress-induced mitochondrial damage.…”

“…It is tempting to speculate that one of the targets of mtHsp70 is mitochondrial p66Shc, whose apoptogenic function might be inhibited when complexed to Hsp70. Notably, transgenic worms that constitutively overexpress the Hsp70 homolog show a life span extension, suggesting that Hsp70 is indeed a genetic determinant of life span in Caenorhabditis (27).…”

Proteostasis in cardiac health and disease

“…Likewise, upregu lation of components of the PQC network prolongs the life of short lived species. Overexpression of HSPs in C. elegans 70,138 and D. melanogaster 68,139 extends their Figure 4 | Impairment of protein quality control and derailment of proteostasis in atrial fibrillation. During stress, chaperones dissociate from the heat shock factor protein 1 (HSF1) complex and bind to unfolded proteins.…”

“…Conversely, knockdown of the master switch of the heat shock response, HSF1, reduces lifespan and sensi tizes proteins to misfolding and aggregation 25,32 . Moreover, overexpression of mitochondrial chaperones HSP70 (HSPA9) 138 Disturbed proteostasis and heart function Cardiac remodelling Derailed proteostasis constitutes a major trigger for dys function of cardiomyocytes, but the ensuing changes in overall cardiac performance involve additional path ways, particularly those involved in cardiac remodel ling. Cardiac remodelling comprises the morphological change of overall heart architecture provoked by pressure or volume overload, or loss of functional cardiomyo cytes.…”

Zinc–gene interaction related to inflammatory/immune response in ageing

“…In vitro study on human fibroblasts undergoing ageing shows that the increment of HSP70 expression is associated with improved functional and survival ability of the cells in terms of increased proteasome activities, increased ability to decompose H 2 O 2 , reduced lipofuscin accumulation and enhanced resistance to ethanol, H 2 O 2 and UV radiation [49]. An overexpression of HSP70 contributes to extend longevity in non-mammalian organism [2,159]. However, old rats show reduced expression and induction of heat shock proteins in response to physiological stresses, including hypertemia [118].…”