Resistance exercise reverses aging in human skeletal muscle

Abstract

Human aging is associated with skeletal muscle atrophy and functional impairment (sarcopenia). Multiple lines of evidence suggest that mitochondrial dysfunction is a major contributor to sarcopenia. We evaluated whether healthy aging was associated with a transcriptional profile reflecting mitochondrial impairment and whether resistance exercise could reverse this signature to that approximating a younger physiological age. Skeletal muscle biopsies from healthy older (N = 25) and younger (N = 26) adult men and women were compared using gene expression profiling, and a subset of these were related to measurements of muscle strength. 14 of the older adults had muscle samples taken before and after a six-month resistance exercise-training program. Before exercise training, older adults were 59% weaker than younger, but after six months of training in older adults, strength improved significantly (P<0.001) such that they were only 38% lower than young adults. As a consequence of age, we found 596 genes differentially expressed using a false discovery rate cut-off of 5%. Prior to the exercise training, the transcriptome profile showed a dramatic enrichment of genes associated with mitochondrial function with age. However, following exercise training the transcriptional signature of aging was markedly reversed back to that of younger levels for most genes that were affected by both age and exercise. We conclude that healthy older adults show evidence of mitochondrial impairment and muscle weakness, but that this can be partially reversed at the phenotypic level, and substantially reversed at the transcriptome level, following six months of resistance exercise training.

Figure 1. Differential Gene expression in physiologically normal individuals with age.

Ordered distance matrix using the HOPACH algorithm of significantly differentially expressed genes in young versus old skeletal muscle (FWER<0.05). Bold lines surround the first level of clustering, with the less bold lines indicating secondary clustering. Green to blue to purple is close to far. B) Medoid gene expression profile of a gene illustrating the expression behavior of cluster 1. C) Medoid gene expression of a gene illustrating the expression behavior of cluster 2.

Figure 2. Exercise reverses a functional decline in the elderly.

Each point represents an individual who underwent strength training as described in the methods. Young individuals had a greater capacity to lift the weights compared to older individuals (p<0.001, non parametric t-test). However, after 6 months training, the older individuals had a marked increase in their ability to carry out the exercise (p<0.0001, paired non-parametric t-test).

Figure 3. Gene expression changes associated with aging are reversed to youthful levels after 6 months of exercise training.

Of the 596 genes associated with age in physiologically normal individuals, 179 of these were statistically significantly associated with a response to exercise at an FDR of 5%. a. Gene Index represents the 179 genes associated with age and exercise. The expression of these genes has been normalized relative to young values (young expression is represented by the dark line drawn across the graph at 1). Each genes average relative expression within the 14 older individuals can be seen relative to younger individuals. Genes that are downregulated with age show a marked reversal to youthful levels with exercise, and genes that are upregulated with age also show the same trend to return to youthful levels in association with exercise. b. Permutation testing of genes associated with exercise and age, to determine statistically significant reversals with exercise. The x axis (log₂) represents the ratio of older subjects post-exercise gene expression compared to young individuals, with 0 being equivalent to “young” gene expression. This resulted in a p-value of <0.02. The conclusion is that the log₂ ratios are much closer to 0 (expression is the same in old-exercise and young) than one would expect by chance (random draw of the 596 genes related to age).

Figure 4. Exercise is more likely to affect “aging” genes than genes not associated with age.

The x-axis (log₂) represents the ratio of post over pre-exercise gene expression among older subjects. The dark solid line represents the distribution of log₂ ratios of exercise (post/pre) among genes that are significantly associated with age. The red line represents the equivalent distribution for those genes not associated with aging. The p-value associated with the difference in distributions is less than 0.0001.