UNC-120/SRF independently controls muscle aging and lifespan in Caenorhabditis elegans.

Aging is commonly defined as the loss of global homeostasis, which results from progressive alteration of all organs function. This model is currently challenged by recent data showing that interventions that extend lifespan do not always increase the overall fitness of the organism. These data suggest the existence of tissue-specific factors that regulate the pace of aging in a cell-autonomous manner. Here, we investigated aging of Caenorhabditis elegans striated muscles at the subcellular and the physiological level. Our data show that muscle aging is characterized by a dramatic decrease in the expression of genes encoding proteins required for muscle contraction, followed by a change in mitochondria morphology, and an increase in autophagosome number. Myofilaments, however, remain unaffected during aging. We demonstrated that the conserved transcription factor UNC-120/SRF regulates muscle aging biomarkers. Interestingly, the role of UNC-120/SRF in the control of muscle aging can be dissociated from its broader effect on lifespan. In daf-2/insulin/IGF1 receptor mutants, which exhibit a delayed appearance of muscle aging biomarkers and are long-lived, disruption of unc-120 accelerates muscle aging but does not suppress the lifespan phenotype of daf-2 mutant. Conversely, unc-120 overexpression delays muscle aging but does not increase lifespan. Overall, we demonstrate that UNC-120/SRF controls the pace of muscle aging in a cell-autonomous manner downstream of the insulin/IGF1 receptor.

Mergoud Dit Lamarche A ，Molin L ，Pierson L ，Mariol MC ，Bessereau JL ，Gieseler K ，Solari F ... -  《-》

DAF-2/insulin IGF-1 receptor regulates motility during aging by integrating opposite signaling from muscle and neuronal tissues.

During aging, preservation of locomotion is generally considered an indicator of sustained good health, in elderlies and in animal models. In Caenorhabditis elegans, mutants of the insulin-IGF-1 receptor DAF2/IIRc represent a paradigm of healthy aging, as their increased lifespan is accompanied by a delay in age-related loss of motility. Here, we investigated the DAF-2/IIRc-dependent relationship between longevity and motility using an auxin-inducible degron to trigger tissue-specific degradation of endogenous DAF-2/IIRc. As previously reported, inactivation of DAF-2/IIRc in neurons or intestine was sufficient to extend the lifespan of worms, whereas depletion in epidermis, germline, or muscle was not. However, neither intestinal nor neuronal depletion of DAF-2/IIRc prevented the age-related loss of motility. In 1-day-old adults, DAF-2/IIRc depletion in neurons reduced motility in a DAF-16/FOXO dependent manner, while muscle depletion had no effect. By contrast, DAF-2 depletion in the muscle of middle-age animals improved their motility independently of DAF-16/FOXO but required UNC-120/SRF. Yet, neuronal or muscle DAF-2/IIRc depletion both preserved the mitochondria network in aging muscle. Overall, these results show that the motility pattern of daf-2 mutants is determined by the sequential and opposing impact of neurons and muscle tissues and can be dissociated from the regulation of the lifespan. This work also provides the characterization of a versatile tool to analyze the tissue-specific contribution of insulin-like signaling in integrated phenotypes at the whole organism level.

Roy C ，Molin L ，Alcolei A ，Solyga M ，Bonneau B ，Vachon C ，Bessereau JL ，Solari F ... -  《-》

End-of-life targeted degradation of DAF-2 insulin/IGF-1 receptor promotes longevity free from growth-related pathologies.

Preferably, lifespan-extending therapies should work when applied late in life without causing undesired pathologies. Reducing insulin/insulin-like growth factor (IGF)-1 signaling (IIS) increases lifespan across species, but the effects of reduced IIS interventions in extreme geriatric ages remains unknown. Using the nematode Caenorhabditis elegans, we engineered the conditional depletion of the DAF-2/insulin/IGF-1 transmembrane receptor using an auxin-inducible degradation (AID) system. This allowed for the temporal and spatial reduction in DAF-2 protein levels at time points after which interventions such as RNAi become ineffective. Using this system, we found that AID-mediated depletion of DAF-2 protein surpasses the longevity of daf-2 mutants. Depletion of DAF-2 during early adulthood resulted in multiple adverse phenotypes, including growth retardation, germline shrinkage, egg retention, and reduced brood size. By contrast, AID-mediated depletion of DAF-2 post-reproduction, or specifically in the intestine in early adulthood, resulted in an extension of lifespan without these deleterious effects. Strikingly, at geriatric ages, when 75% of the population had died, AID-mediated depletion of DAF-2 protein resulted in a doubling in lifespan. Thus, we provide a proof-of-concept that even close to the end of an individual's lifespan, it is possible to slow aging and promote longevity.

Venz R ，Pekec T ，Katic I ，Ciosk R ，Ewald CY ... -  《eLife》

Roles of the developmental regulator unc-62/Homothorax in limiting longevity in Caenorhabditis elegans.

Van Nostrand EL ，Sánchez-Blanco A ，Wu B ，Nguyen A ，Kim SK ... -  《-》

DAF-16/FoxO directly regulates an atypical AMP-activated protein kinase gamma isoform to mediate the effects of insulin/IGF-1 signaling on aging in Caenorhabditis elegans.

Tullet JM ，Araiz C ，Sanders MJ ，Au C ，Benedetto A ，Papatheodorou I ，Clark E ，Schmeisser K ，Jones D ，Schuster EF ，Thornton JM ，Gems D ... -  《PLoS Genetics》