A causal role for mitochondrial DNA (mtDNA) mutagenesis in mammalian aging is supported by recent studies demonstrating that the mtDNA mutator mouse, harboring a defect in the ...proofreading-exonuclease activity of mitochondrial polymerase gamma, exhibits accelerated aging phenotypes characteristic of human aging, systemic mitochondrial dysfunction, multisystem pathology, and reduced lifespan. Epidemiologic studies in humans have demonstrated that endurance training reduces the risk of chronic diseases and extends life expectancy. Whether endurance exercise can attenuate the cumulative systemic decline observed in aging remains elusive. Here we show that 5 mo of endurance exercise induced systemic mitochondrial biogenesis, prevented mtDNA depletion and mutations, increased mitochondrial oxidative capacity and respiratory chain assembly, restored mitochondrial morphology, and blunted pathological levels of apoptosis in multiple tissues of mtDNA mutator mice. These adaptations conferred complete phenotypic protection, reduced multisystem pathology, and prevented premature mortality in these mice. The systemic mitochondrial rejuvenation through endurance exercise promises to be an effective therapeutic approach to mitigating mitochondrial dysfunction in aging and related comorbidities.
Changes in fat content have been associated with dietary restriction (DR), but whether they play a causal role in mediating various responses to DR remains unknown. We demonstrate that upon DR, ...Drosophila melanogaster shift their metabolism toward increasing fatty-acid synthesis and breakdown, which is required for various responses to DR. Inhibition of fatty-acid synthesis or oxidation genes specifically in the muscle tissue inhibited life-span extension upon DR. Furthermore, DR enhances spontaneous activity of flies, which was found to be dependent on the enhanced fatty-acid metabolism. This increase in activity was found to be at least partially required for the life-span extension upon DR. Overexpression of adipokinetic hormone (dAKH), the functional ortholog of glucagon, enhances fat metabolism, spontaneous activity, and life span. Together, these results suggest that enhanced fat metabolism in the muscle and physical activity play a key role in the protective effects of DR.
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► DR enhances both fatty-acid synthesis and utilization in Drosophila melanogaster ► Enhanced fatty-acid metabolism in the muscle increases activity and life span ► Increased physical activity upon DR is required for life-span extension ► Overexpression of dAKH enhances fat metabolism, activity, and life span
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.
Many vital processes in the eye are under circadian regulation, and circadian dysfunction has emerged as a potential driver of eye aging. Dietary restriction is one of the most robust ...lifespan-extending therapies and amplifies circadian rhythms with age. Herein, we demonstrate that dietary restriction extends lifespan in Drosophila melanogaster by promoting circadian homeostatic processes that protect the visual system from age- and light-associated damage. Altering the positive limb core molecular clock transcription factor, CLOCK, or CLOCK-output genes, accelerates visual senescence, induces a systemic immune response, and shortens lifespan. Flies subjected to dietary restriction are protected from the lifespan-shortening effects of photoreceptor activation. Inversely, photoreceptor inactivation, achieved via mutating rhodopsin or housing flies in constant darkness, primarily extends the lifespan of flies reared on a high-nutrient diet. Our findings establish the eye as a diet-sensitive modulator of lifespan and indicates that vision is an antagonistically pleiotropic process that contributes to organismal aging.
Abstract Microgravity is associated with immunological dysfunction, though the mechanisms are poorly understood. Here, using single-cell analysis of human peripheral blood mononuclear cells ...(PBMCs) exposed to short term (25 hours) simulated microgravity, we characterize altered genes and pathways at basal and stimulated states with a Toll-like Receptor-7/8 agonist. We validate single-cell analysis by RNA sequencing and super-resolution microscopy, and against data from the Inspiration-4 (I4) mission, JAXA (Cell-Free Epigenome) mission, Twins study, and spleens from mice on the International Space Station. Overall, microgravity alters specific pathways for optimal immunity, including the cytoskeleton, interferon signaling, pyroptosis, temperature-shock, innate inflammation (e.g., Coronavirus pathogenesis pathway and IL-6 signaling), nuclear receptors, and sirtuin signaling. Microgravity directs monocyte inflammatory parameters, and impairs T cell and NK cell functionality. Using machine learning, we identify numerous compounds linking microgravity to immune cell transcription, and demonstrate that the flavonol, quercetin, can reverse most abnormal pathways. These results define immune cell alterations in microgravity, and provide opportunities for countermeasures to maintain normal immunity in space.
Inhibition of DAF-2 (insulin-like growth factor 1 IGF-1 receptor) or RSKS-1 (S6K), key molecules in the insulin/IGF-1 signaling (IIS) and target of rapamycin (TOR) pathways, respectively, extend ...lifespan in Caenorhabditis elegans. However, it has not been clear how and in which tissues they interact with each other to modulate longevity. Here, we demonstrate that a combination of mutations in daf-2 and rsks-1 produces a nearly 5-fold increase in longevity that is much greater than the sum of single mutations. This synergistic lifespan extension requires positive feedback regulation of DAF-16 (FOXO) via the AMP-activated protein kinase (AMPK) complex. Furthermore, we identify germline as the key tissue for this synergistic longevity. Moreover, germline-specific inhibition of rsks-1 activates DAF-16 in the intestine. Together, our findings highlight the importance of the germline in the significantly increased longevity produced by daf-2 rsks-1, which has important implications for interactions between the two major conserved longevity pathways in more complex organisms.
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•The daf-2 rsks-1 double mutant shows synergistic lifespan extension in C. elegans•AMPK mediates positive feedback regulation of DAF-16 in daf-2 rsks-1•Germline tissue is a key tissue in modulating this synergistic longevity•Inhibiting rsks-1 in the germline leads to cell-nonautonomous activation of DAF-16
The evolutionarily conserved insulin/insulin-like growth factor 1 (IGF-1) signaling and ribosomal S6 kinase (S6K) play a critical role in aging. Here, Chen, Kapahi, and colleagues show that simultaneous inhibition of DAF-2 (insulin/IGF-1 receptor) and RSKS-1 (S6K) leads to a nearly 5-fold synergistic lifespan extension in Caenorhabditis elegans. The mechanism of this exceptional longevity involves a positive feedback regulation of DAF-16 (FOXO transcription factor) via AMP-activated protein kinase (AMPK). Further studies highlight the germ line as a critical tissue for the daf-2 rsks-1-mediated synergistic longevity.
Summary
The roundworm C. elegans is widely used as an aging model, with hundreds of genes identified that modulate aging (Kaeberlein et al., 2002. Mech. Ageing Dev.123, 1115–1119). The development ...and bodyplan of the 959 cells comprising the adult have been well described and established for more than 25 years (Sulston & Horvitz, 1977. Dev. Biol.56, 110–156; Sulston et al., 1983. Dev. Biol.100, 64–119.). However, morphological changes with age in this optically transparent animal are less well understood, with only a handful of studies investigating the pathobiology of aging. Age‐related changes in muscle (Herndon et al., 2002. Nature419, 808–814), neurons (Herndon et al., 2002), intestine and yolk granules (Garigan et al., 2002. Genetics161, 1101–1112; Herndon et al., 2002), nuclear architecture (Haithcock et al., 2005. Proc. Natl Acad. Sci. USA102, 16690–16695), tail nuclei (Golden et al., 2007. Aging Cell6, 179–188), and the germline (Golden et al., 2007) have been observed via a variety of traditional relatively low‐throughput methods. We report here a number of novel approaches to study the pathobiology of aging C. elegans. We combined histological staining of serial‐sectioned tissues, transmission electron microscopy, and confocal microscopy with 3D volumetric reconstructions and characterized age‐related morphological changes in multiple wild‐type individuals at different ages. This enabled us to identify several novel pathologies with age in the C. elegans intestine, including the loss of critical nuclei, the degradation of intestinal microvilli, changes in the size, shape, and cytoplasmic contents of the intestine, and altered morphologies caused by ingested bacteria. The three‐dimensional models we have created of tissues and cellular components from multiple individuals of different ages represent a unique resource to demonstrate global heterogeneity of a multicellular organism.
Vitamin D has multiple roles, including the regulation of bone and calcium homeostasis. Deficiency of 25-hydroxyvitamin D, the major circulating form of vitamin D, is associated with an increased ...risk of age-related chronic diseases, including Alzheimer’s disease, Parkinson’s disease, cognitive impairment, and cancer. In this study, we utilized Caenorhabditis elegans to examine the mechanism by which vitamin D influences aging. We found that vitamin-D3-induced lifespan extension requires the stress response pathway genes skn-1, ire-1, and xbp-1. Vitamin D3 (D3) induced expression of SKN-1 target genes but not canonical targets of XBP-1. D3 suppressed an important molecular pathology of aging, that of widespread protein insolubility, and prevented toxicity caused by human β-amyloid. Our observation that D3 improves protein homeostasis and slows aging highlights the importance of maintaining appropriate vitamin D serum levels and may explain why such a wide variety of human age-related diseases are associated with vitamin D deficiency.
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•Vitamin D metabolism is conserved between nematodes and mammals•Vitamin D prevents the age-dependent accumulation of SDS-insoluble proteins•Vitamin D enhances lifespan and protein homeostasis via IRE-1, XBP-1, and SKN-1
Maintenance of protein homeostasis is crucial to cellular health and contributes significantly to the lifespan of organisms. Mark et al. demonstrate that vitamin D supplementation promotes protein homeostasis and slows aging in the nematode, C. elegans. These findings identify a mechanism by which vitamin D influences aging.
Reducing protein synthesis slows growth and development but can increase adult life span. We demonstrate that knockdown of eukaryotic translation initiation factor 4G (eIF4G), which is downregulated ...during starvation and dauer state, results in differential translation of genes important for growth and longevity in C. elegans. Genome-wide mRNA translation state analysis showed that inhibition of IFG-1, the C. elegans ortholog of eIF4G, results in a relative increase in ribosomal loading and translation of stress response genes. Some of these genes are required for life span extension when IFG-1 is inhibited. Furthermore, enhanced ribosomal loading of certain mRNAs upon IFG-1 inhibition was correlated with increased mRNA length. This association was supported by changes in the proteome assayed via quantitative mass spectrometry. Our results suggest that IFG-1 mediates the antagonistic effects on growth and somatic maintenance by regulating mRNA translation of particular mRNAs based, in part, on transcript length.
► IFG-1 inhibition enhances ribosomal loading of stress response mRNAs ► IFG-1 decreases during fasting, leading to increased resistance to starvation ► Some stress response genes are critical for life span extension upon IFG-1 inhibition ► Differential ribosomal loading upon IFG-1 inhibition is associated with mRNA length
Lithium (Li+) has been used to treat mood affect disorders, including bipolar, for decades. This drug is neuroprotective and has several identified molecular targets. However, it has a narrow ...therapeutic range and the one or more underlying mechanisms of its therapeutic action are not understood. Here we describe a pharmacogenetic study of Li+ in the nematode Caenorhabditis elegans. Exposure to Li+ at clinically relevant concentrations throughout adulthood increases survival during normal aging (up to 46% median increase). Longevity is extended via a novel mechanism with altered expression of genes encoding nucleosome-associated functions. Li+ treatment results in reduced expression of the worm ortholog of LSD-1 (T08D10.2), a histone demethylase; knockdown by RNA interference of T08D10.2 is sufficient to extend longevity (∼25% median increase), suggesting Li+ regulates survival by modulating histone methylation and chromatin structure.
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