Lifelong Reduction in Complex IV Induces Tissue Specific Metabolic Effects But Does Not Reduce Lifespan or Healthspan in Mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA419234 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Loss of SURF1, a Complex IV assembly protein, was reported to increase lifespan in mice despite dramatically lower cytochrome oxidase (COX) activity. Consistent with this, our previous studies found advantageous changes in metabolism (reduced adiposity, increased insulin sensitivity and mitochon-drial biogenesis) in Surf1-/- mice. The lack of deleterious phenotypes in Surf1-/- mice is contrary to the hypothesis that mitochondrial dysfunction contributes to aging. We found only a modest (non-significant) extension of lifespan (7% median, 16% maximum) and no change in healthspan indices in Surf1-/- vs Surf1+/+ mice despite substantial decreases in COX activity (22-87% across tissues). Dietary restriction (DR) increased median lifespan in both Surf1+/+ and Surf1-/- mice (36 and 19%, respectively). We measured gene expression, metabolites and targeted expression of key metabolic proteins in adi-pose tissue, liver and brain in Surf1+/+ and Surf1-/- mice. Gene expression was differentially regulated in a tissue specific pattern. We found that many proteins and metabolites are downregulated in Surf1-/- adipose tissue and reversed by DR, while in brain most metabolites that changed were elevated in Surf1-/- mice. Finally, mitochondrial unfolded protein response (UPRmt)-associated proteins were not uniformly altered by age or genotype, suggesting the UPRmt is not a key player in aging or the response to reduced COX activity. While the changes in gene expression and metabolism may represent com-pensatory responses to mitochondrial stress, the important outcome of this study is that lifespan and healthspan are not compromised in Surf1-/- mice, suggesting that mitochondrial deficiencies may not be a critical determinant of lifespan.
2020-11-20 | GSE107191 | GEO
Project description:Loss of SURF1, a Complex IV assembly protein, was reported to increase lifespan in mice despite dramatically lower cytochrome oxidase (COX) activity. Consistent with this, our previous studies found advantageous changes in metabolism (reduced adiposity, increased insulin sensitivity, and mitochondrial biogenesis) in Surf1-/- mice. The lack of deleterious phenotypes in Surf1-/- mice is contrary to the hypothesis that mitochondrial dysfunction contributes to aging. We found only a modest (nonsignificant) extension of lifespan (7% median, 16% maximum) and no change in healthspan indices in Surf1-/- vs. Surf1+/+ mice despite substantial decreases in COX activity (22%-87% across tissues). Dietary restriction (DR) increased median lifespan in both Surf1+/+ and Surf1-/- mice (36% and 19%, respectively). We measured gene expression, metabolites, and targeted expression of key metabolic proteins in adipose tissue, liver, and brain in Surf1+/+ and Surf1-/- mice. Gene expression was differentially regulated in a tissue-specific manner. Many proteins and metabolites are downregulated in Surf1-/- adipose tissue and reversed by DR, while in brain, most metabolites that changed were elevated in Surf1-/- mice. Finally, mitochondrial unfolded protein response (UPRmt )-associated proteins were not uniformly altered by age or genotype, suggesting the UPRmt is not a key player in aging or in response to reduced COX activity. While the changes in gene expression and metabolism may represent compensatory responses to mitochondrial stress, the important outcome of this study is that lifespan and healthspan are not compromised in Surf1-/- mice, suggesting that not all mitochondrial deficiencies are a critical determinant of lifespan.
| S-EPMC6052393 | biostudies-literature
Project description:Targeting NAT10 enhances healthspan and lifespan in a mouse model of human accelerated aging syndrome.
2018-03-22 | E-MTAB-6578 | biostudies-arrayexpress
Project description:Various anti-aging interventions exhibit potential in extending lifespan, yet most of these interventions are inefficacy or even have deleterious effects on healthspan. Ginkgolide B (GB) is a Ginkgo biloba-derived small molecule that reduces aging-related morbidities; however, the effects of GB on healthspan and longevity remain elusive. Here, we report that continuous oral GB administration in mice starting at 20 months extended their lifespan by 20% and reduced tumour incidence. Besides, GB administration significantly improved healthspan evidenced by enhancement in muscle quality, physical performance, grip strength, metabolism, frailty index, systemic inflammation, and senescence. Moreover, GB administration ameliorated aging-related pathologies without any apparent adverse effects. Single-nucleus RNA sequencing (snRNA-seq) revealed that GB improved aging-associated abnormal cell-type composition, intracellular signalling pathways, and cell-cell communication in skeletal muscles. GB also reduced the levels of aging-induced novel Runx1+ type 2B myonuclei, which are associated with apoptotic burden and aging-related signatures. Runx1 derived senescence, as shown by gain- and loss-of-function assays. Together, a new function of GB in extending the healthspan in aging is identified, which contributes to lifespan extension. The senomorphic effects of GB on the multifactorial aging process may provide new prospects for achieving healthy aging and longevity extension.
2024-10-31 | GSE254739 | GEO
Project description:Molecular aging reflects the time-dependent accumulation of cellular damage and loss of essential cellular functions. FOXO transcription factors and their downstream targets play critical roles in the response to aging-associated cellular damage. Here, we identify and characterize a novel FOXO-regulated stress response gene, Oxidative Stress Responsive Serine-rich Protein 1 (OSER1), whose level of expression dramatically influences lifespan in Bombyx mori, Caenorhabditis elegans, and Drosophila. Overexpression of OSER1 also enhances resistance to oxidative stress, starvation, and heat shock, whereas depletion increases susceptibility to these stressors. In humans, common OSER1 genetic variants are associated with longevity. These data show that OSER1 modulates the oxidative stress response and suggest that OSER1 is a potent positive regulator of lifespan and healthspan in multiple species.
2024-07-25 | PXD036579 | Pride
Project description:Since healthspan-extending interventions such as caloric restriction or fasting robustly promote lipid catabolism, we investigated how lifespan and healthspan were affected by increased lipid catabolism via bmm (brummer, FBgn0036449), the major triglyceride hydrolase in Drosophila. Global overexpression of bmm strongly promoted lifespan extension as well as numerous markers of healthspan, including increased female fecundity, fertility maintenance, preserved locomotion activity, increased mitochondrial biogenesis and oxidative metabolism. Increased Bmm robustly upregulated the heat shock protein 70 (Hsp70) family of proteins, which equipped the flies with higher resistance to heat, cold, and ER stress via improved proteostasis. Overexpression of bmm recapitulated major physiological changes associated with dietary restriction (DR) and conveyed its effects through dSir2. Taken together, these data show that bmm overexpression has broad beneficial effects on healthspan, and implicate lipolysis as a key node underlying the beneficial effects of dietary interventions known to improve healthspan.
2022-09-27 | GSE178816 | GEO
Project description:Aging is a major international concern and brings with it formidable socioeconomical and healthcare challenges. An attainable approach to improve general health in humans is using small molecules. Tomatidine, a natural compound abundant in unripe tomatoes, inhibits aging-related skeletal muscle atrophy in mice. Here we show that tomatidine extends lifespan and healthspan in the aging animal model C. elegans, which shares many major longevity pathways with those of mammals. Tomatidine improves behaviors related to healthspan, including increased pharyngeal pumping and swimming movement, and also reduces deterioration of muscle cells in worms. Microarray, imaging, and behavioral analysis reveal that tomatidine maintains mitochondrial homeostasis through mitochondrial biogenesis and PINK-1/DCT-1-dependent mitophagy. Mechanistically, tomatidine induces mitochondrial hormesis by mildly inducing ROS production, which in turn activates the cellular antioxidant response SKN-1/Nrf2 pathway, followed by increased mitophagy in worms, primary rat neurons, and human cells. Our data suggest that tomatidine may delay some physiological aspects of aging, and points to new approaches for pharmacological interventions towards diseases of aging.
2017-08-21 | GSE85237 | GEO
Project description:Lysosomes are cytoplasmic organelles that are central for the degradation of macromolecules to maintain cellular homeostasis and health. Here, we discovered an adaptive lysosomal transcriptional response that we termed the lysosomal stress response (LySR). Typified by the induction of a large group of transcripts involved in lysosomal function and proteolysis, the LySR can be triggered by silencing of specific vacuolar H+-ATPase subunits in Caenorhabditis elegans. Notably, LySR activation enhances the clearance of protein aggregates in worm models of Alzheimer's and Huntington’s disease and amyotrophic lateral sclerosis, thereby boosting fitness and extending lifespan, a response that is controlled by the GATA transcription factor, ELT-2. Activating the LySR pathway may therefore represent an attractive mechanism to reduce protein aggregation and, as such, extend healthspan.
2023-02-03 | GSE196022 | GEO
Project description:Lysosomes are cytoplasmic organelles that are central for the degradation of macromolecules to maintain cellular homeostasis and health. Here, we discovered an adaptive lysosomal transcriptional response that we termed the lysosomal stress response (LySR). Typified by the induction of a large group of transcripts involved in lysosomal function and proteolysis, the LySR can be triggered by silencing of specific vacuolar H+-ATPase subunits in Caenorhabditis elegans. Notably, LySR activation enhances the clearance of protein aggregates in worm models of Alzheimer's and Huntington’s disease and amyotrophic lateral sclerosis, thereby boosting fitness and extending lifespan, a response that is controlled by the GATA transcription factor, ELT-2. Activating the LySR pathway may therefore represent an attractive mechanism to reduce protein aggregation and, as such, extend healthspan.
2023-02-03 | GSE196021 | GEO
Project description:Ribose-5-phosphate isomerase A (RPIA) is a rate-limiting enzyme, which connects oxidative phase to non-oxidative phase and mediates redox homeostasis in pentose phosphate pathway (PPP). Here, we report that spatially and temporally limited knockdown of rpia-1 prolongs lifespan and improves healthspan in C. elegans, reflecting the evolutionarily conserved phenotypes observed in Drosophila. We first confirmed that both ubiquitous (in N2) and pan-neuronal (in TU3401) knockdown of rpia-1 enhance tolerance to oxidative stress, reduce polyglutamine aggregation, and improve the deteriorated body bending rate caused by polyglutamine aggregation. Next, we observed that both rpia-1 knockdown conditions enhance lifespan. In addition, rpia-1 knockdown in glutamatergic or cholinergic neurons was sufficient to increase lifespan. Besides the regulation of healthspan through the elevation of NADPH levels, we also identified novel molecular mechanisms that contribute to the longevity effect. Our results showed that rpia-1 reduction was accompanied by induction of autophagic flux, activation of AMPK, and inhibition of TOR signaling. Importantly, the lifespan extension by rpia-1 knockdown required the activation of autophagy and AMPK pathways, and reduced TOR sig-naling. Moreover, the RNA-seq data from the two longlived rpia-1 knockdown strains supported our experimental findings and reveal potential downstream targets, which may play key roles in this intervention. Together, our data disclose the specific spatial and temporal conditions and the underlying molecular mechanisms of rpia-1 knockdown-mediated longevity in C. elegans. These findings may facilitate the development of translational medicine and the improvement of lon-gevity research.
2023-01-25 | GSE216697 | GEO