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  1. Evaluation Summary:

    This paper is of interest to researchers studying muscle function in the nematode C. elegans and to researchers interested in muscle aging in humans. The work documents the importance of C. elegans alh-6, which encodes a proline catabolic gene, in limiting muscle stress and maintaining locomotory function in aging nematodes. Further work implicates GWAS SNPs in the human homolog ALDH4A1 as potential determinants of specific muscle decline indicators. The suggestion of a conserved role for ALH-6 in aging humans could underlie establishment of a useful biomarker for older age muscle-associated health. However, while the work expands on and reinforces findings in C. elegans, it does not yet rigorously demonstrate a role for ALDH4A1 in muscle function in aging humans.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

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  2. Reviewer #1 (Public Review):

    In this manuscript entitled "Genetic variation in ALDH4A1 predicts muscle health over the lifespan and across species", the authors showed that many loss-of-function mutations in alh-6, which encodes evolutionarily conserved mitochondrial proline dehydrogenase, contributed to age-dependent declines in muscle functions in C. elegans. They also performed gene-wide association study (GeneWAS) in human cohorts and showed that genetic variants in ALDH4A1, a human homolog of C. elegans alh-6, correlated with age-dependent changes in muscle function. This paper's approach is very elegant and provides valuable information regarding how genetic variants in a single gene conserved in C. elegans and humans can affect muscle aging.

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  3. Reviewer #2 (Public Review):

    Declining muscle function characterizes aging across animals. In this study, Villa and Stuhr et al. investigate a potentially conserved role for ALDH4A1, the human homolog of C. elegans alh-6, in age-related muscle decline. Previous work from the same group showed that alh-6 was necessary to avoid shortening of lifespan in C. elegans fed certain diets through a mechanism that involves improved mitochondrial function in the muscle. In the current paper, the authors establish that alh-6 controls muscle function in aging C. elegans. Further, the authors search for evidence for a potentially conserved role for ALDH4A1 in human muscle health. Promisingly, the authors succeed in identifying multiple SNPs in the ALDH4A1 locus. However, in the current state, some important C. elegans data are missing, and the human genetics analyses fall short of conclusively advancing the notion that ALDH4A1 modulates muscle aging in humans.

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  4. Reviewer #3 (Public Review):

    Villa et. al. conduct a genetic screen in C. elegans to identify mutants which activate the oxidative stress response transcription factor, skn-1, and its target gene gst-4 selectively in muscle during aging. From the screen, they identified 96 mutants showing activation of skn-1, and all of the mutants map to a single gene, alh-6. The alh-6 gene encodes the worm ortholog of ALDH4A1, which is required for the degradation of the amino acid proline. When ALDH4A1 is mutated in worms, the toxic metabolite 1-pyrroline-5-carboxylate accumulates from proline degradation and leads to oxidative stress and mitochondrial dysfunction in the muscle. The identification of so many alleles of a single gene from a genetic screen suggests that alh-6 and proline degradation plays an essential role in preventing oxidative stress in muscle during aging.

    To build upon these findings, the authors use data from the Health and Retirement Study to determine if variants in the human ALDH4A1 gene are associated with aspects of muscle function during aging. They study the association of 53 single nucleotide polymorphisms in the ALDH4A1 region with a variety of phenotypes including muscle strength, declines in muscle strength over time, gait speed, and a number of functional measures. They find that specific polymorphisms are associated with some of the phenotypes but not others.

    Based on the human data showing age-related declines in muscle function, Villa et. al. return to using the nematode model, and show that the majority of the alh-6 alleles are associated with declines in worm mobility in aging adult worms (day 3 adults) but not in L4 larval worms. These findings suggest that alh-6 has a selective impact on muscle function during aging, but not during larval life.

    Strengths of the work include the combined use of C. elegans experiments and human data to study the role of the ALDH4A1 gene in muscle function during aging. The C. elegans experiments particularly use an extensive genetic screen, and then complementation studies followed by gene sequencing with 96 distinct strains to demonstrate that all of the identified mutations map to a single gene. These point to a critical role for alh-6 in preventing oxidative stress in aging worm muscle.

    Weaknesses of the work focus on the human studies. A wide range of strength, gait speed, and functional phenotypes are explored by the authors. However, some of the phenotypes, such as IADL1 which involves the ability to take medication, use the telephone, and manage money, have little connection with muscle function. Instead these IADL abilities are more closely tied to memory and cognitive abilities. Alternately, other phenotypes like arm lifting, are influenced greatly by health factors separate from muscle function, like shoulder arthritis or rotator cuff injuries, which are common in older individuals. Additionally, the ability to walk across a room, walk 1 block, walk several blocks, and then jog 1 mile represent progressive stages in community mobility. Finding that a gene is associated with difficulty walking across a room but not mobility of greater distances is surprising. Hence, the broad focus of the selected phenotypes leads to the data seemingly being equally likely to be due to chance than a muscle aging effect. This concern could be potentially addressed by utilizing other available datasets to see if the initial findings can be replicated in a separate population.

    Beyond the phenotypes selected for study, there are assumptions made by the authors that could be better discussed. While in C. elegans alh-6 plays a critical role for proline metabolism in muscle, in humans ALDH4A1 is expressed more highly in liver and kidney than in muscle, and ALDH4A1 is also expressed fairly broadly at a lower level. Seeing changes in muscle strength, gait speed, or other phenotypes could be due to changes in muscle function, or could be secondary to diseases like diabetes or chronic kidney disease in another organ system. Acknowledging these limitations does not minimize their findings but reflects the greater complexity of human aging.

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