A time to fast Di Francesco, Andrea; Di Germanio, Clara; Bernier, Michel ...
Science,
11/2018, Letnik:
362, Številka:
6416
Journal Article
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Nutrient composition and caloric intake have traditionally been used to devise optimized diets for various phases of life. Adjustment of meal size and frequency have emerged as powerful tools to ...ameliorate and postpone the onset of disease and delay aging, whereas periods of fasting, with or without reduced energy intake, can have profound health benefits. The underlying physiological processes involve periodic shifts of metabolic fuel sources, promotion of repair mechanisms, and the optimization of energy utilization for cellular and organismal health. Future research endeavors should be directed to the integration of a balanced nutritious diet with controlled meal size and patterns and periods of fasting to develop better strategies to prevent, postpone, and treat the socioeconomical burden of chronic diseases associated with aging.
The global population of individuals over the age of 65 is growing at an unprecedented rate and is expected to reach 1.6 billion by 2050. Most older individuals are affected by multiple chronic ...diseases, leading to complex drug treatments and increased risk of physical and cognitive disability. Improving or preserving the health and quality of life of these individuals is challenging due to a lack of well‐established clinical guidelines. Physicians are often forced to engage in cycles of “trial and error” that are centered on palliative treatment of symptoms rather than the root cause, often resulting in dubious outcomes. Recently, geroscience challenged this view, proposing that the underlying biological mechanisms of aging are central to the global increase in susceptibility to disease and disability that occurs with aging. In fact, strong correlations have recently been revealed between health dimensions and phenotypes that are typical of aging, especially with autophagy, mitochondrial function, cellular senescence, and DNA methylation. Current research focuses on measuring the pace of aging to identify individuals who are “aging faster” to test and develop interventions that could prevent or delay the progression of multimorbidity and disability with aging. Understanding how the underlying biological mechanisms of aging connect to and impact longitudinal changes in health trajectories offers a unique opportunity to identify resilience mechanisms, their dynamic changes, and their impact on stress responses. Harnessing how to evoke and control resilience mechanisms in individuals with successful aging could lead to writing a new chapter in human medicine.
Finding a reference metric for the rate of biological aging is key to understanding the molecular nature of the aging process. Defining and validating this metric in humans opens the door to a new kind of medicine that will overcome the limitation of current disease definitions. We will then be able to approach health in a global perspective and bring life course preventative measures to the center of attention.
The phenomenon of aging is an intrinsic feature of life. Accordingly, the possibility to manipulate it has fascinated humans likely since time immemorial. Recent evidence is shaping a picture where ...low caloric regimes and exercise may improve healthy senescence, and several pharmacological strategies have been suggested to counteract aging. Surprisingly, the most effective interventions proposed to date converge on only a few cellular processes, in particular nutrient signaling, mitochondrial efficiency, proteostasis, and autophagy. Here, we critically examine drugs and behaviors to which life- or healthspan-extending properties have been ascribed and discuss the underlying molecular mechanisms.
The most effective antiaging interventions proposed to date converge on only a few cellular processes, in particular nutrient signaling, mitochondrial efficiency, proteostasis, and autophagy.
Mitochondria are known to be functional organelles, but their role as a signaling unit is increasingly being appreciated. The identification of a short open reading frame (sORF) in the mitochondrial ...DNA (mtDNA) that encodes a signaling peptide, humanin, suggests the possible existence of additional sORFs in the mtDNA. Here we report a sORF within the mitochondrial 12S rRNA encoding a 16-amino-acid peptide named MOTS-c (mitochondrial open reading frame of the 12S rRNA-c) that regulates insulin sensitivity and metabolic homeostasis. Its primary target organ appears to be the skeletal muscle, and its cellular actions inhibit the folate cycle and its tethered de novo purine biosynthesis, leading to AMPK activation. MOTS-c treatment in mice prevented age-dependent and high-fat-diet-induced insulin resistance, as well as diet-induced obesity. These results suggest that mitochondria may actively regulate metabolic homeostasis at the cellular and organismal level via peptides encoded within their genome.
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•MOTS-c is a 16-amino-acid peptide encoded in the mitochondrial genome•MOTS-c targets muscle and regulates metabolism via the folate-purine-AMPK pathway•MOTS-c mediates mitochondrial regulation of insulin and metabolic homeostasis•MOTS-c protects against age- and diet-dependent insulin resistance and obesity
Lee et al. identify a novel bioactive mitochondrial-derived peptide (MOTS-c) encoded in the mitochondrial DNA that regulates metabolic homeostasis. MOTS-c regulates insulin sensitivity and metabolic homeostasis via AMPK, and prevents age-dependent and high-fat-diet-induced insulin resistance, as well as diet-induced obesity.
Circulating levels of undercarboxylated and bioactive osteocalcin double during aerobic exercise at the time levels of insulin decrease. In contrast, circulating levels of osteocalcin plummet early ...during adulthood in mice, monkeys, and humans of both genders. Exploring these observations revealed that osteocalcin signaling in myofibers is necessary for adaptation to exercise by favoring uptake and catabolism of glucose and fatty acids, the main nutrients of myofibers. Osteocalcin signaling in myofibers also accounts for most of the exercise-induced release of interleukin-6, a myokine that promotes adaptation to exercise in part by driving the generation of bioactive osteocalcin. We further show that exogenous osteocalcin is sufficient to enhance the exercise capacity of young mice and to restore to 15-month-old mice the exercise capacity of 3-month-old mice. This study uncovers a bone-to-muscle feedforward endocrine axis that favors adaptation to exercise and can reverse the age-induced decline in exercise capacity.
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•Bone via the hormone osteocalcin improves muscle function during exercise•Circulating osteocalcin levels decrease in aging mice, monkeys, and humans•Osteocalcin promotes muscle uptake and utilization of glucose and fatty acids•Osteocalcin promotes muscle IL-6 secretion during exercise
Mera et al. show that the bone-derived hormone osteocalcin is necessary for optimum exercise capacity and that this hormone decreases with aging in mice, monkeys, and humans of both genders. Osteocalcin promotes muscle uptake and utilization of glucose and lipids during exercise and greatly improves the exercise capacity of old mice.
Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the ...oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/β-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD+ and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD+ levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible.
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•A specific decline in mitochondrially encoded genes occurs during aging in muscle•Nuclear NAD+ levels regulate mitochondrial homeostasis independently of PGC-1α/β•Declining NAD+ during aging causes pseudohypoxia, which disrupts OXPHOS function•Raising nuclear NAD+ in old mice reverses pseudohypoxia and metabolic dysfunction
Aging disrupts an NAD+-dependent nuclear-mitochondrial communication pathway, causing a decline in the mitochondrially encoded oxidative phosphorylation components relative to nuclear-encoded components. Raising NAD+ levels in old mice alleviates the pseudohypoxic conditions that disrupt the communication pathway, reversing this mitochondrial defect.
MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast, we find that Myc haploinsufficient (Myc+/–) mice exhibit increased lifespan. They show resistance to ...several age-associated pathologies, including osteoporosis, cardiac fibrosis, and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism. Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR, and S6K activities. In contrast to observations in other longevity models, Myc+/– mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a significant impact on longevity and multiple aspects of mammalian healthspan.
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•Reduction of Myc expression in mice promotes longevity•Lower Myc levels benefit multiple organs and physiological processes•Decreased Myc activity triggers changes in core nutrient and energy-sensing pathways•Lower Myc levels do not cause apparent changes in stress management pathways
Reduced expression of MYC increases lifespan in mice and benefits multiple aspects related to the aging process without apparent developmental trade-offs or changes in stress management pathways.
Immune-based interventions are promising strategies to achieve long-term cancer-free survival. Fasting was previously shown to differentially sensitize tumors to chemotherapy while protecting normal ...cells, including hematopoietic stem and immune cells, from its toxic side effects. Here, we show that the combination of chemotherapy and a fasting-mimicking diet (FMD) increases the levels of bone marrow common lymphoid progenitor cells and cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs), leading to a major delay in breast cancer and melanoma progression. In breast tumors, this effect is partially mediated by the downregulation of the stress-responsive enzyme heme oxygenase-1 (HO-1). These data indicate that FMD cycles combined with chemotherapy can enhance T cell-dependent targeted killing of cancer cells both by stimulating the hematopoietic system and by enhancing CD8+-dependent tumor cytotoxicity.
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•The FMD is as effective as fasting in sensitizing tumors to chemotherapy•FMD cycles promote the enrichment of common lymphoid progenitor cells•FMD/doxorubicin increase tumor immunogenicity and tumor-infiltrating lymphocytes•HO-1 plays a key role in the FMD-induced chemosensitization of breast cancer cells
Di Biase et al. show that combining a fasting-mimicking diet with chemotherapy increases the levels of bone marrow common lymphoid progenitor cells and cytotoxic CD8+ tumor-infiltrating lymphocytes, delaying tumor progression. In breast tumors, this effect is partially mediated by downregulating HO-1.
According to a commonly held view, the obesity pandemic is caused by overconsumption of modern, highly palatable, energy-dense processed foods, exacerbated by a sedentary lifestyle. However, obesity ...rates remain at historic highs, despite a persistent focus on eating less and moving more, as guided by the energy balance model (EBM). This public health failure may arise from a fundamental limitation of the EBM itself. Conceptualizing obesity as a disorder of energy balance restates a principle of physics without considering the biological mechanisms that promote weight gain. An alternative paradigm, the carbohydrate-insulin model (CIM), proposes a reversal of causal direction. According to the CIM, increasing fat deposition in the body—resulting from the hormonal responses to a high-glycemic-load diet—drives positive energy balance. The CIM provides a conceptual framework with testable hypotheses for how various modifiable factors influence energy balance and fat storage. Rigorous research is needed to compare the validity of these 2 models, which have substantially different implications for obesity management, and to generate new models that best encompass the evidence.
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