Methods of both modestly impairing and modestly improving mitochondrial function have been shown to slow aging in short-lived species such as flies and nematodes, albeit for different reasons. Every cell contains hundreds of mitochondria that undertake the energetic process of producing adenosine triphosphate (ATP), a chemical energy store molecule used to power cell operations. The chemistry of ATP manufacture produces damaging oxidative molecules as a side-effect, but that flux of oxidative molecules is also a signal that a cell reacts to with increased maintenance, such as an increase in autophagy to clear out damaged proteins and structures. Better mitochondrial function is directly helpful to the cell, but modestly worse mitochondrial function can inspire a sufficient increase in cell maintenance to still come out ahead. Better cell function throughout the body tends to translate to improved health and slowed aging.
In today’s open access paper, researchers report on their assessment of one of the many approaches to modestly impair mitochondrial function, by impeding the uptake of calcium ions through the mitochondrial membrane. As is the case for a number of such approaches, this adjustment increases the production of oxidative molecules in mitochondria, causing the cell to react with improved maintenance. Interestingly, this harms survival in early life, which explains why evolution has not provided species with mitochondria altered in this way to slow aging and improve overall life span.
Enhancing Late-Life Survival and Mobility via Mitohormesis by Reducing Mitochondrial Calcium Levels
Mitochondrial calcium (Ca2+) homeostasis plays a critical role in aging and cellular fitness. In the search for novel antiaging approaches, we explored how genetic and pharmacological inhibition of mitochondrial Ca2+ uptake influences the lifespan and health of Caenorhabditis elegans. Using live-cell imaging, we demonstrate that RNA interference-mediated knockdown of mcu-1, the nematode ortholog of the mitochondrial Ca2+ uniporter (MCU), reduces mitochondrial Ca2+ levels, thereby extending lifespan and preserving motility during aging, while compromising early-life survival.
This longevity benefit requires intervention before day 14 and coincides with a transient increase in reactive oxygen species (ROS), which activates pathways involving pmk-1, daf-16, and skn-1, orthologs of human p38 mitogen-activated protein kinase (p38 MAPK), forkhead box O (FOXO), and nuclear factor erythroid 2-related factor 2 (NRF2), respectively. This pathway promotes antioxidant defense mechanisms and preserves mitochondrial structure and function during aging, maintaining larger, more interconnected mitochondria and restoring the oxidized/reduced nicotinamide adenine dinucleotide (NAD+/NADH) ratio and oxygen consumption rates to youthful levels.
Pharmacological inhibition of mitochondrial Ca2+ uptake using the MCU inhibitor mitoxantrone mirrors the effects of mcu-1 knockdown, extending lifespan and improving fitness in aged nematodes. In human foreskin fibroblasts, short-term mitoxantrone treatment also transiently elevates ROS production and induces enhanced expression and activity of antioxidant defense enzymes, underscoring the translational relevance of findings from nematodes to human cells. Our findings suggest that modulation of mitochondrial Ca2+ uptake induces mitohormesis through ROS-mediated signaling, promoting improved longevity and healthspan in nematodes, with possible implications for healthy aging in humans.
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