Augmentation of the heat shock axis during exceptional longevity in Ames dwarf mice

Trivedi, Rachana; Knopf, Bailey; Tripathi, Jitendra Kumar; Rakoczy, Shar; Manocha, Gunjan D.; Brown‐Borg, Holly M.; Jurivich, Donald A.

doi:10.1007/s11357-021-00362-w

Cited by 5 publications

(15 citation statements)

References 80 publications

(95 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with other studies on aging and other tissue, HSF1 -DNA binding levels in brain from older mice decrease from 30 to 50% relative to brains from younger mice (3M). Unlike other studies, however, we nd that the age -dependent decline in brain HSF1 -DNA binding occurs at the 12M juncture rather than the 20-24M period of time in other mouse tissue [Trivedi et al 2021]. By contrast, brain samples from long lived Dwarf mice demonstrate a steady increase in HSF1-DNA binding over the life span with most robust levels of HSF1 -DNA binding observed in the 22M when compared to 3M brains.…”

Section: Discussioncontrasting

confidence: 91%

Disrupted HSF1 regulation in normal and exceptional brain aging

Trivedi

Knopf

Rakoczy

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Brain aging is a major risk factor for cognitive diseases including Alzheimer’s disease (AD) and vascular dementia. The rate of aging and appearance of age-related pathology are modulated by stress responses and repair pathways that gradually decline with age. However, recent reports indicate that exceptional longevity sustains and may even enhance the stress response. Whether normal and exceptional aging result in either attenuated or enhanced stress responses across all organs is unknown. This question arises from our understanding that biological age differs from chronological age and evidence that the rate of aging varies between organs. Thus, stress responses may differ between organs, especially if they are composed of poorly regenerative tissue and accumulate a lifespan of damaged proteins. To answer these questions, we assessed age-dependent changes in brain stress responses with normal aged wild type and long-lived Dwarf mice. Results from this study show that normal aging unfavorably impacts activation of the brain heat shock (HS) axis with key changes noted in the transcription factor, HSF1, that include decreased protein levels, changes in its phosphorylation and altered co-factors. Exceptional aging appears to preserve and strengthen many elements of HSF1 activation in the brain. These results support the possibility that reconstitution of aging brain stress responses requires a multi – factorial approach that addresses HSF1 protein levels, its DNA binding, and regulatory elements such as phosphorylation and protein interactions.

show abstract

Section: Discussioncontrasting

confidence: 91%

Disrupted HSF1 regulation in normal and exceptional brain aging

Trivedi

Knopf

Rakoczy

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Mammalian aging correlates with proteostatic collapse, including compromised molecular chaperone levels and functions 16 , 17 , 53 – 55 . Since cellular senescence is a crucial biological process underlying aging 56 , we investigated whether below threshold levels of Hsp90 trigger accelerated senescence.…”

Section: Resultsmentioning

confidence: 99%

“…We conclude from this series of experiments that mammalian organisms and cells that cannot fine-tune Hsp90 to the physiologically required levels might experience accelerated aging and premature death, such as those 90αKO 90βHET embryos, which fail to increase Hsp90β levels. Several molecular chaperones, including Hsp90, are known to be reduced during aging in mammals, including in humans 53 – 55 . We found that the mTOR inhibitor and anti-aging drug rapamycin 57 , 58 reduces the heat stress-induced senescence marker p21 in Hsp90α/β KO HEK293T cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Translational reprogramming in response to accumulating stressors ensures critical threshold levels of Hsp90 for mammalian life

et al. 2022

View full text Add to dashboard Cite

The cytosolic molecular chaperone Hsp90 is essential for eukaryotic life. Although reduced Hsp90 levels correlate with aging, it was unknown whether eukaryotic cells and organisms can tune the basal Hsp90 levels to alleviate physiologically accumulated stress. We have investigated whether and how mice adapt to the deletion of three out of four alleles of the two genes encoding cytosolic Hsp90, with one Hsp90β allele being the only remaining one. While the vast majority of such mouse embryos die during gestation, survivors apparently manage to increase their Hsp90β protein to at least wild-type levels. Our studies reveal an internal ribosome entry site in the 5’ untranslated region of the Hsp90β mRNA allowing translational reprogramming to compensate for the genetic loss of Hsp90 alleles and in response to stress. We find that the minimum amount of total Hsp90 required to support viability of mammalian cells and organisms is 50–70% of what is normally there. Those that fail to maintain a threshold level are subject to accelerated senescence, proteostatic collapse, and ultimately death. Therefore, considering that Hsp90 levels can be reduced ≥100-fold in the unicellular budding yeast, critical threshold levels of Hsp90 have markedly increased during eukaryotic evolution.

show abstract

“…Given the loss of HSF-DNA binding with usual aging and its gain during exceptional aging (Jurivich et al 2020 ; Trivedi et al 2021 ) we examined HSF1 protein and mRNA levels between the two aging groups of mice. Figure 1 D shows that HSF1 protein levels at 3 M steadily decline in 12 M and 22 M old wild type brain by 47% and another 9% respectively (p = 0.005 for 3 vs 12 M and p = 0.5029 for 12 vs 22 M).…”

Section: Resultsmentioning

confidence: 99%

Disrupted HSF1 regulation in normal and exceptional brain aging

Trivedi,

Knopf,

Rakoczy

et al. 2023

Biogerontology

Self Cite

View full text Add to dashboard Cite

Brain aging is a major risk factor for cognitive diseases such as Alzheimer’s disease (AD) and vascular dementia. The rate of aging and age-related pathology are modulated by stress responses and repair pathways that gradually decline with age. However, recent reports indicate that exceptional longevity sustains and may even enhance the stress response. Whether normal and exceptional aging result in either attenuated or enhanced stress responses across all organs is unknown. This question arises from our understanding that biological age differs from chronological age and evidence that the rate of aging varies between organs. Thus, stress responses may differ between organs and depend upon regenerative capacity and ability to manage damaged proteins and proteotoxicity. To answer these questions, we assessed age-dependent changes in brain stress responses with normally aged wild type and long-lived Dwarf mice. Results from this study show that normal aging unfavorably impacts activation of the brain heat shock (HS) axis with key changes noted in the transcription factor, HSF1, and its regulation. Exceptional aging appears to preserve and strengthen many elements of HSF1 activation in the brain. These results support the possibility that reconstitution of aging brain stress responses requires a multi-factorial approach that addresses HSF1 protein levels, its DNA binding, and regulatory elements such as phosphorylation and protein interactions.

show abstract

Augmentation of the heat shock axis during exceptional longevity in Ames dwarf mice

Cited by 5 publications

References 80 publications

Disrupted HSF1 regulation in normal and exceptional brain aging

Disrupted HSF1 regulation in normal and exceptional brain aging

Translational reprogramming in response to accumulating stressors ensures critical threshold levels of Hsp90 for mammalian life

Disrupted HSF1 regulation in normal and exceptional brain aging

Contact Info

Product

Resources

About