Genetic variation in ALDH4A1 is associated with muscle health over the lifespan and across species.

ABSTRACT

The influence of genetic variation on the aging process, including the incidence and severity of age-related diseases, is complex. Here, we define the evolutionarily conserved mitochondrial enzyme ALH-6/ALDH4A1 as a predictive biomarker for age-related changes in muscle health by combining Caenorhabditis elegans genetics and a gene-wide association scanning (GeneWAS) from older human participants of the US Health and Retirement Study (HRS). In a screen for mutations that activate oxidative stress responses, specifically in the muscle of C. elegans, we identified 96 independent genetic mutants harboring loss-of-function alleles of alh-6, exclusively. Each of these genetic mutations mapped to the ALH-6 polypeptide and led to the age-dependent loss of muscle health. Intriguingly, genetic variants in ALDH4A1 show associations with age-related muscle-related function in humans. Taken together, our work uncovers mitochondrial alh-6/ALDH4A1 as a critical component to impact normal muscle aging across species and a predictive biomarker for muscle health over the lifespan.

Ageing is inevitable, but what makes one person 'age well' and another decline more quickly remains largely unknown. While many aspects of ageing are clearly linked to genetics, the specific genes involved often remain unidentified. Sarcopenia is an age-related condition affecting the muscles. It involves a gradual loss of muscle mass that becomes faster with age, and is associated with loss of mobility, decreased quality of life, and increased risk of death. Around half of all people aged 80 and over suffer from sarcopenia. Several lifestyle factors, especially poor diet and lack of exercise, are associated with the condition, but genetics is also involved the condition accelerates more quickly in some people than others, and even fit, physically active individuals can be affected. To study the genetics of conditions like sarcopenia, researchers often use animals like flies or worms, which have short generation times but share genetic similarities with humans. For example, the worm Caenorhabditis elegans has equivalents of several human muscle genes, including the gene alh-6. In worms, alh-6 is important for maintaining energy supply to the muscles, and mutating it not only leads to muscle damage but also to premature ageing. Given this insight, Villa, Stuhr, Yen et al. wanted to determine if variation in the human version of alh-6, ALDH4A1, also contributes to individual differences in muscle ageing and decline in humans. Evaluating variation in this gene required a large amount of genetic data from older adults. These were taken from a continuous study that follows >35,000 older adults. Importantly, the study collects not only information on gene sequences but also measures of muscle health and performance over time for each individual. Analysis of these genetic data revealed specific small variations in the DNA of ALDH4A1, all of which associated with reduced muscle health. Follow-up experiments in worms used genetic engineering techniques to test how variation in the worm alh-6 gene could influence age-related health. The resulting mutant worms developed muscle problems much earlier than their normal counterparts, supporting the role of alh-6/ALDH4A1 in determining muscle health across the lifespan of both worms and humans. These results have identified a key influencer of muscle health during ageing in worms, and emphasize the importance of validating effects of genetic variation among humans during this process. Villa, Stuhr, Yen et al. hope that this study will help researchers find more genetic 'markers' of muscle health, and ultimately allow us to predict an individual's risk of sarcopenia based on their genetic make-up.