Scientists revealed potential targets to delay motor aging

Contrary to common opinion, the increase in life expectancy worldwide over the past few decades has rarely been accompanied by an increase in health span. The key to good aging is to prevent or delay the decline of vital physiological processes since the functional deterioration of numerous organs and tissues defines aging.

The quality of life for elderly people is closely correlated with their level of motor independence. But from worms to humans, motor aging is a common, conserved biological process that can cause frailty, a loss of motor independence, falling, and even death. However, the regulators of motor aging have not yet been comprehensively investigated.

In recent work, researchers developed a quick and effective Caenorhabditis elegans (C. elegans) genome-wide screening test to find putative regulators of motor aging comprehensively. Caenorhabditis elegans, a nematode, is a common animal model for aging research. Like humans, C. elegans has motor decline with aging, primarily characterized by histological and functional decrease of motor neurons and muscles.

This work provides a comprehensive overview of the genes affecting motor aging and shows that VPS34 is a conserved target for delaying and treating motor aging.

Scientists noted, “To our knowledge, VPS34 is the first reported gene that simultaneously regulates neurotransmission of motor neurons and muscle integrity during aging, likely through cell type-specific mechanisms. Thus, it is a promising target that can be exploited to improve both aged neurons and muscle, as demonstrated by our SAR405 treatment experiments.”

“Although the motor function improvement in our behavioral assays can be mainly attributed to the improved neurotransmission of motor neurons, additional assays to specifically test the functional improvement of muscle after VPS34 inhibition could further delineate the benefits of our treatment strategy.”

Researchers further clarified the molecular mechanism underpinning better motor neuron activity following VPS34 suppression. Numerous genetic studies revealed that two processes involving VPS34—autophagy and endocytosis—are unlikely to significantly impact VPS34-regulated motor aging. Instead, inhibiting VPS34 causes a change in the ratio of PI(3)P-PI-PI(4)P conversion, leading to higher concentrations of PI(4)P, which is necessary for exocytosis and, as a result, more synaptic vesicle release.

Scientists noted, “It is worth noting that partial inhibition but not complete blockade of VPS34 is sufficient to delay or ameliorate motor aging. Previous studies have shown that germline knockout of vps-34 in nematodes and mice causes developmental arrest.”

“Conditional knockout of Vps34 in mice causes degeneration and failure of organs [30,56–59]. Since VPS34 is the only class III PI3K regulating the PI(3)P level, it is conceivable that it may be required in multiple organs or cell types. We carefully examined the worms from vps-34 RNAi, qx546, and SAR405 partial inhibition groups and did not observe deleterious effects regarding brood size, overall development, and lifespan. Thus, our observation that partial inhibition of VPS34 delays or ameliorates neuronal and muscular aging is not contradictory to previous studies, but rather offers a viable treatment strategy to promote healthy aging.”

Journal Reference:

Zhongliang Hu, Yamei Luo, et al. Partial inhibition of class III PI3K VPS-34 ameliorates motor aging and prolongs health span. PLOS Biology. DOI: 10.1371/journal.pbio.3002165

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