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Overactive cell metabolism linked to biological aging

Overactive Cell Metabolism Linked to Biological Aging
Meta-analysis of human studies reveals increased energy expenditure and shortened lifespan in primary mitochondrial diseases. a Overall conceptual model linking mtDNA- and nDNA-related OxPhos defects to impaired metabolic efficiency at the cellular level, impacting whole-body resting energy expenditure and clinical outcomes. b Skeletal muscle biopsy with individual muscle fibers stained with cytochrome c oxidase/succinate dehydrogenase (COX/SDH) histochemistry to reveal functional (brown) and respiratory chain deficient (blue) mitochondria. In the affected cell (middle), three sub-regions showing low, intermediate, and high mtDNA mutation load were captured by laser capture microdissection and subjected to quantitative PCR analysis as in ref. 117. Subcellular regions with high mtDNA mutation load show elevated mtDNA density, which is predicted to increase the energetic cost due to mitochondrial biogenesis and turnover processes. WT, wild type. c Meta-analysis of human mitochondrial disease cohorts showing elevated resting heart rate (n = 104 controls, 111 patients), d catecholamines (urinary-Cohort 3 and blood-Cohort 6) at rest or during fixed-intensity exercise (n = 38 controls, 19 patients), e whole-body oxygen consumption measured by indirect calorimetry at rest or during the response to mild exercise challenge; one before training, two after training. Slope refers to the rate of increase in VO2 relative to work rate, where a higher slope indicates increased energetic cost for a given work rate (n = 56 controls, 78 patients). f Body mass index (BMI) across mitochondrial disease cohorts and compared to relevant national averages (USA, UK, and Italy combined) (n = 285 controls, 174 patients). g Average life expectancy in individuals with mitochondrial diseases relative to the national average (n = 301 patients). Data are means ± SEM, with % difference between mitochondrial disease and control group were available. h Mortality (age at death) over 10 years (2010–2020) in Cohort 17 compared to national averages for women and men (n = 109 patients). See Table 1 for cohort details. Total n = 225 healthy controls, 690 patients. Only aggregate group means (with or without a measure of variance) were available for some cohorts, so individual participant data is not shown. Standardized effect sizes are quantified as Hedges’ g (g). Overall group comparisons were performed by paired t tests (c and f) or one-sample t tests (d and e), *p < 0.05, **p < 0.01, ****p < 0.0001.

Why do cells, and by extension humans, age? The answer may have a lot to do with mitochondria, the organelles that supply cells with energy. Though that idea is not new, direct evidence in human cells had been lacking. Until now.

In a study published Jan. 12 in Communications Biology, a team led by Columbia University researchers has discovered that with impaired mitochondria respond by kicking into higher gear and expending more energy. While this adaptation—called hypermetabolism—enhances the cells' short-term survival, it comes at a high cost: a dramatic increase in the rate at which the cells age.

"The findings were made in cells from patients with rare , yet they may also have relevance for other conditions that affect mitochondria, including , inflammatory conditions, and infections," says principal investigator Martin Picard, Ph.D., associate professor of behavioral medicine (in psychiatry and neurology) at Columbia University Vagelos College of Physicians and Surgeons.

"In addition, hypermetabolism may be a key reason why most cells deteriorate as we get older."

Hypermetabolic cells age faster

It was generally assumed that mitochondrial defects (which impair the conversion of food sources into ) would force cells to slow their in an effort to conserve energy. However, by analyzing and energy consumption in cells from patients with mitochondrial diseases, the researchers found that cells with impaired mitochondria double their energy expenditure. Moreover, re-analyzing data from hundreds of patients with different mitochondrial diseases showed that mitochondrial defects also increase the energetic cost of living at the whole-body level.

Although this energy boost keeps cells running, it also degrades the cell's telomeres (caps that protect the ends of our chromosomes) and activates stress responses and inflammation. The net effect accelerates biological aging.

"When cells expend more energy to make proteins and other substances essential for short-term survival, they're likely stealing resources from processes that ensure long-term survival, like maintaining telomeres," says Gabriel Sturm, a graduate student and lead author on this study.

Hypermetabolism, fatigue, and aging

This hypermetabolic state could explain why people with mitochondrial diseases experience fatigue and exercise intolerance, among other symptoms. "To make up for the extra energy use in your cells, your body 'tells' you not to overexert yourself, to conserve energy. We likely see the same dynamic as people age and their vitality diminishes," Picard says.

The study doesn't point to any new remedies for patients with mitochondrial diseases, which are currently not treatable, but it does reinforce the current recommendations for patients to move more. "That may seem counterintuitive, since if you're more active, you're going to expend more energy and possibly make your symptoms worse," Sturm says. "But exercise is known to increase the efficiency of an organism. An individual who runs, for example, uses less energy to sustain basic bodily processes than someone who is not physically active."

Improving organismal efficiency, which would lower energy use in the cells and improve fatigue and other symptoms, may partially explain the health benefits of exercise in patients with mitochondrial diseases and otherwise healthy people.

In their search for new treatments for mitochondrial diseases, researchers should focus on hypermetabolism, Picard says. "Although do impair the ability of cells to produce energy, energy deficiency may not be the primary disease initiator. Our study shows these defects increase . To move the needle therapeutically, we may need to target hypermetabolism. We need more research to know if that would work."

Hypermetabolism is also common to other diseases. If increased cellular plays a causal role in driving the aging process, targeting hypermetabolism may be a way to improve fatigue, improve people's quality of life, or even to slow biological aging.

More information: Gabriel Sturm et al, OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases, Communications Biology (2023). DOI: 10.1038/s42003-022-04303-x

Citation: Overactive cell metabolism linked to biological aging (2023, January 12) retrieved 26 May 2024 from
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