SAM, SAH and C. elegans longevity: insights from a partial AHCY deficiency model

Area of Science:

• Gerontology and Aging Research
• Molecular Biology and Genetics
• Biochemistry and Metabolism

Background:

• S-adenosylhomocysteine (SAH) supplementation is known to extend lifespan in various model organisms.
• Understanding the precise mechanisms by which SAH influences aging is crucial for developing interventions.
• The enzyme S-adenosylhomocysteine hydrolase (AHCY-1) plays a key role in SAH metabolism.

Purpose of the Study:

• To investigate the impact of endogenous S-adenosylhomocysteine (SAH) levels on aging processes in Caenorhabditis elegans.
• To characterize a novel C. elegans model harboring a mutation in the AHCY-1 gene, mimicking a human pathogenic mutation.
• To elucidate the molecular pathways involved in SAH-mediated lifespan extension.

Main Methods:

• Generation of a C. elegans model with the AHCY-1 Y145C variant, analogous to the human AHCY Y143C mutation.
• Measurement of S-adenosylhomocysteine (SAH) and S-adenosylmethionine (SAM) levels in mutant and wild-type worms.
• Assessment of aging phenotypes, including lifespan, and genetic analysis involving AMPK, VRK-1, and DAF-16.

Main Results:

• The AHCY-1 Y145C mutation led to delayed aging and extended lifespan in C. elegans.
• Mutant worms exhibited moderately increased SAH levels and decreased SAM levels.
• Lifespan extension was dependent on AMP-activated protein kinase (AMPK), VRK-1, and the DAF-16 transcription factor.

Conclusions:

• The balance between SAM and SAH is critical for regulating lifespan in C. elegans.
• Impaired SAH hydrolysis, leading to altered SAH/SAM ratios, can promote longevity.
• The generated AHCY-1 partial deficiency model serves as a valuable tool for studying methionine metabolism and aging.