Circadian gene variants and the skeletal muscle circadian clock contribute to the evolutionary divergence in longevity across Drosophila populations

Abstract

Organisms use endogenous clocks to adapt to the rhythmicity of the environment and to synchronize social activities. Although the circadian cycle is implicated in aging, it is unknown whether natural variation in its function contributes to differences in lifespan between populations and whether the circadian clock of specific tissues is key for longevity. We have sequenced the genomes of Drosophila melanogaster strains with exceptional longevity that were obtained via multiple rounds of selection from a parental strain. Comparison of genomic, transcriptomic, and proteomic data revealed that changes in gene expression due to intergenic polymorphisms are associated with longevity and preservation of skeletal muscle function with aging in these strains. Analysis of transcription factors differentially modulated in long-lived versus parental strains indicates a possible role of circadian clock core components. Specifically, there is higher period and timeless and lower cycle expression in the muscle of strains with delayed aging compared to the parental strain. These changes in the levels of circadian clock transcription factors lead to changes in the muscle circadian transcriptome, which includes genes involved in metabolism, proteolysis, and xenobiotic detoxification. Moreover, a skeletal muscle-specific increase in timeless expression extends lifespan and recapitulates some of the transcriptional and circadian changes that differentiate the long-lived from the parental strains. Altogether, these findings indicate that the muscle circadian clock is important for longevity and that circadian gene variants contribute to the evolutionary divergence in longevity across populations.

Antagonistic control of myofiber size and muscle protein quality control by the ubiquitin ligase UBR4 during aging

“…We recently found that the muscle transcriptome and proteome become progressively disconnected with aging in Drosophila 8 . By comparing the changes induced by UBR4 loss at the transcript level versus the protein level, we found an overall low correlation ( r 2 = 0.207) at 6 months of age, as expected based on the molecular function of UBR4, which is a ubiquitin ligase that modulates the degradation of target proteins, independently from their mRNA levels.…”

“…Muscle functional assays were done as before 8 . In brief, flight capacity was assessed by releasing flies into a clear box and counting the number of flies that could fly and that could not (i.e., that dropped immediately downward) to derive the percentage of flies not flying.…”

“…In addition to disease-associated muscle wasting, age-related loss of muscle mass and function (sarcopenia) is an important medical issue. As for disease-associated muscle wasting, preventing age-related skeletal muscle dysfunction has important systemic consequences, and extends healthspan and longevity [6][7][8] . However, despite the important functions of ubiquitin ligases in disease-associated muscle wasting, the role that ubiquitin ligases have in sarcopenia is largely unexplored.…”

Analysis of proteostasis during aging with western blot of detergent-soluble and insoluble protein fractions

“…Tissues from Drosophila and mice of the desired genotypes and ages, and treatment of HKE293 cells and human brain organoids should be done according to the specific experimental requirements and following procedures as described in our and other recent studies ( Hunt et al., 2019a ; Hunt et al., 2021 ; Hunt et al., 2019b ; Hunt et al., 2015 ; Rai et al., 2021 ). Once obtained, these tissues can be examined following the procedures described below.…”

Aging with rhythmicity. Is it possible? Physical exercise as a pacemaker

“…Whereas, the aging is characterized by disruption on circadian rhythms, the opposite is true too. The chronic deraignment on circadian clock reduces the longevity on Drosophila [ 38 , 39]. In humans, the shift-workers show loss of circadian rhythms and consequently higher risk to develop metabolic abnormalities and early aging observed by shorter of leukocytes telomere length [ 40 ].…”