Beneficial Effects Of Dietary Restriction Research Articles

Dietary deprivation reduces the deleterious effects of carbaryl on the survival and activity of both catalase and acetylcholinesterase in earthworms

Dietary restriction (DR) and dietary deprivation (DD) have been shown to be significantly beneficial in terms of lifespan gains and stress alleviation in invertebrate and vertebrate species. Such beneficial effects, however, have yet to be clearly assessed in the presence of chemical stressors. We conducted a comparative evaluation of the toxicity of carbaryl in Eisenia fetida individuals subjected to a full diet (FD), DR and DD. For 14 days, groups of ten worms subjected to FD received 5 g oatmeal, those subjected to DR received 2.5 g oatmeal, and those subjected to DD received 0 g oatmeal weekly. We evaluated concentrations of 0, 7, 14 and 28 mg carbaryl.kg−1 soil and measured effects on survival, reproduction, biomass and biomarkers (Catalase- CAT and acetylcholine esterase- AChE). Carbaryl caused a total inhibition of reproduction in all the treatments. For each diet level, the 14-day LC50 s were higher than 28 mg.kg−1, but the 14-day LC20 s for the earthworms subjected to FD, DR, and DD were 11.24, 20.51 and > 28 mg.kg−1, respectively. This showed that the toxicity of carbaryl consistently decreased with the reduction in nutrients. Carbaryl caused a significant weight loss in the worms subjected to FD in the 7 mg.kg−1 treatment (P = 0.0065). Such weight loss was not found in any of the other treatments and diets. Both CAT and AChE were significantly inhibited in the two highest treatments (P = 0.0071 and P = 0.0073, respectively). Interestingly, the earthworms subjected to DD showed relatively lower biomarker inhibition, indicating a greater tolerance to oxidative and neurotoxic stresses in these starved earthworms. For all endpoints investigated, aside from reproduction, the starved earthworms fared better under carbaryl toxicity than those given the other diets. Overall, a positive correlation was observed between the amount of food and chemical toxicity as mortality rates, AChE and CAT inhibition increased with the increased amount of nutrients given to the worms. These results show that, in the presence of a chemical stressor, the beneficial effects of DR and DD were variably manifest for select lifecycle parameters and biomarker responses, further suggesting dietary reduction as a non-genetic intervention that could help extend lifespan and alleviate stress even under a chemical insult.

Gene expression changes in cerebellum induced by dietary restriction.

Dietary restriction (DR) is a well-established universal anti-aging intervention, and is neuroprotective in multiple models of nervous system disease, including models with cerebellar pathology. The beneficial effects of DR are associated with a rearrangement of gene expression that modulate metabolic and cytoprotective pathways. However, the effect of DR on the cerebellar transcriptome remained to be fully defined. Here we analyzed the effect of a classical 30% DR protocol on the transcriptome of cerebellar cortex of young-adult male mice using RNAseq. We found that about 5% of expressed genes were differentially expressed in DR cerebellum, the far majority of whom showing subtle expression changes. A large proportion of down-regulated genes are implicated in signaling pathways, in particular pathways associated with neuronal signaling. DR up regulated pathways in large part were associated with cytoprotection and DNA repair. Analysis of the expression of cell-specific gene sets, indicated a strong enrichment of DR down genes in Purkinje cells, while genes specifically associated with granule cells did not show such a preferential down-regulation. Our data show that DR may have a clear effect on the cerebellar transcriptome inducing a mild shift from physiology towards maintenance and repair, and having cell-type specific effects.

RNA PROCESSING MECHANISMS DURING AGING AND CALORIC RESTRICTION

Abstract Caloric restriction (CR), a reduction in caloric intake without malnutrition, was first described in the 1930s and is a robust model to extend lifespan. While the specific mechanisms that produce delayed aging are still unknown, work has demonstrated the importance of metabolism – dysregulated mitochondrial metabolism is an aging hallmark, while CR upregulates energy metabolism. Crucially, transcriptional regulation plays a key role in implementing this metabolic program although details are still unclear. Splicing factors that are required for the beneficial effects of dietary restriction in nematodes have been identified, and large-scale exon usage changes have been observed across the metabolic network engaged by CR in various tissues from non-human primates, suggesting a translational mechanism that might contribute to how CR delays aging. We will discuss the landscape of RNA processing across multiple organism, tissue, and intervention contexts and provide a broad perspective of how RNA processing contributes to enhanced longevity.

Dietary Restriction against Parkinson's Disease: What We Know So Far.

Dietary restriction (DR) is defined as a moderate reduction in food intake while avoiding malnutrition. The beneficial effects of DR are being increasingly acknowledged in aging and in a series of age-related neurodegenerative disorders, for example, Parkinson’s disease (PD). To date, the pathogenesis of PD remains elusive and there is no cure for it in spite of intensive research over decades. In this review, we summarize the current knowledge on the efficacy of DR on PD, focusing on the underlying mechanisms involving general metabolism, neuroendocrinolgy, neuroinflammation, gut microbiome, and so on. We anticipate that this review will provide future perspectives for PD prevention and treatment.

Dietary Protein Restriction Improves Metabolic Dysfunction in Patients with Metabolic Syndrome in a Randomized, Controlled Trial

Dietary restriction (DR) reduces adiposity and improves metabolism in patients with one or more symptoms of metabolic syndrome. Nonetheless, it remains elusive whether the benefits of DR in humans are mediated by calorie or nutrient restriction. This study was conducted to determine whether isocaloric dietary protein restriction is sufficient to confer the beneficial effects of dietary restriction in patients with metabolic syndrome. We performed a prospective, randomized controlled dietary intervention under constant nutritional and medical supervision. Twenty-one individuals diagnosed with metabolic syndrome were randomly assigned for caloric restriction (CR; n = 11, diet of 5941 ± 686 KJ per day) or isocaloric dietary protein restriction (PR; n = 10, diet of 8409 ± 2360 KJ per day) and followed for 27 days. Like CR, PR promoted weight loss due to a reduction in adiposity, which was associated with reductions in blood glucose, lipid levels, and blood pressure. More strikingly, both CR and PR improved insulin sensitivity by 62.3% and 93.2%, respectively, after treatment. Fecal microbiome diversity was not affected by the interventions. Adipose tissue bulk RNA-Seq data revealed minor changes elicited by the interventions. After PR, terms related to leukocyte proliferation were enriched among the upregulated genes. Protein restriction is sufficient to confer almost the same clinical outcomes as calorie restriction without the need for a reduction in calorie intake. The isocaloric characteristic of the PR intervention makes this approach a more attractive and less drastic dietary strategy in clinical settings and has more significant potential to be used as adjuvant therapy for people with metabolic syndrome.

Dietary restriction in multiple sclerosis: evidence from preclinical and clinical studies

Dietary restriction (DR) interventions, which encompass both chronic and intermittent reductions in energy intake, are emerging as potential therapeutic approaches for dampening neuroinflammation and demyelination in multiple sclerosis (MS). Mechanisms mediating the beneficial effects of DR include the regulation of pro- and anti-inflammatory signalling molecules and gut microbiome remodelling. This article summarises the preclinical evidence supporting the role of DR in attenuating disease in animal models of MS and the developing clinical evidence indicating the safety and feasibility of such DR interventions in people with MS (pwMS).

Glycerol‐3‐Phosphate Phosphatase/ PGP: A Novel Dietary Restriction Mimetic Enzyme that Protects from Glucotoxicity and Prolongs Healthspan in C. elegans

Metabolic stress due to nutrient excess and lipid accumulation is at the root of many age-associated disorders and the identification of therapeutic targets that mimic the beneficial effects of calorie restriction has clinical importance. Here, using C. elegans as a model organism, we studied the roles of a recently discovered enzyme at the heart of metabolism in mammalian cells, glycerol 3-phosphate phosphatase (G3PP) (gene name Pgp) that hydrolyzes glucose-derived glycerol-3-phosphate (Gro3P) to glycerol. Gro3P is a key metabolite that regulates flux of various metabolic pathways and particularly, the glycerolipid/fatty acid (GL/FA) cycle associated with obesity, type-2-diabetes, and cardiometabolic disorders. We identify three Pgp homologues in C. elegans (pgph1, pgph-2, and pgph-3) and demonstrate in vivo that their protein products have G3PP activity, essential for glycerol synthesis and contributes to stress responses and healthy aging. Hyperosmotic and high glucose stresses induce pgph transcripts, glycerol production, and salt stress adaptation in a PGPH-dependent manner. Using targeted metabolomics, we find that Gro3P accumulates in pgph mutant animals in basal conditions and more prominently following salt and glucose stresses, while most intermediary metabolites are rarely altered by PGPH loss. Using an unbiased transcription factors RNAi screen, we further identify transcriptional regulators of pgph-2 and pgph-3 salt-mediated expression. Loss of PGPH increases fat deposition, exacerbates glucotoxicity, decreases resistance to various stresses, shortens median lifespan and decreases healthspan parameters. Importantly, pgph-2 overexpression reduces fat deposition with age at basal and glucose excess conditions without restricting animal feeding or decreasing reproduction. Overexpression of pgph-2 improves healthspan and protects from glucotoxicity retarding age-related locomotor decline in normal and high glucose conditions. Strikingly, our data suggest that the overexpression of pgph-2 partly mimics the beneficial effects of dietary restriction. Overall, the results demonstrate that G3PP/PGP is a novel evolutionary conserved regulator of glucose and fat metabolism that protects against nutrient and environmental stresses and is involved in glucose detoxification and healthy aging.

In Contrast to Dietary Restriction, Application of Resveratrol in Mice Does not Alter Mouse Major Urinary Protein Expression.

Resveratrol (RSV) supplementation in mice has been discussed as partly mimicking the beneficial effects of dietary restriction (DR). However, data on putative benefits from resveratrol application in mice and other model organisms including humans is contradictory. Mouse major urinary proteins (MUPs) are a family of proteins that are expressed in rodent liver and secreted via urine. Impacting (mating) behavior and pheromone communication, they are severely down-regulated upon DR. We carried out two studies in C57BL/6Rj mice where RSV was either supplemented via diet or injected intraperitoneally for 8 weeks. Contrary to −40% DR, RSV did not decrease total MUP protein expression or Mup (amongst others Mup3, Mup5, Mup6, Mup15, and Mup20) mRNA levels in mouse liver when compared to ad-libitum (AL)-fed controls. Since inhibitory glucocorticoid response elements can be found in Mup promoters, we also measured glucocorticoid receptor (GR) levels in nuclear hepatic extracts. Consistent with differential MUP expression, we observed more nuclear GR in DR mice than in RSV-supplemented and AL control mice with no difference between RSV and AL. These findings point to the notion that, in mice, RSV does not mimic DR in terms of differential MUP expression.

Metabolic memory of dietary restriction ameliorates DNA damage and adipocyte size in mouse visceral adipose tissue.

Dietary restriction (DR) is thought to exert its beneficial effects on healthspan at least partially by a senolytic and senostatic action, i.e. by reducing frequencies of cells with markers of DNA damage and senescence in multiple tissues. Due to its importance in metabolic and inflammation regulation, fat is a prime tissue for health span determination as well as a prime target for DR. We aimed to determine here whether the beneficial effects of DR would be retained over a subsequent period of ad libitum (AL) feeding. Male mice were kept under either 40% DR or AL feeding regimes from 3 to 12 months of age and then either switched back to the opposite feeding regimen or kept in the same state for another 3 months. Visceral adipose tissue from 4 to 5 mice per group for all conditions was analysed for markers of senescence (adipocyte size, γH2A.X, p16, p21) and inflammation (e.g. IL-6, TNFα, IL-1β) using immuno-staining or qPCR. Macrophages were detected by immunohistochemistry. We found that both 9 and 12 months DR (long term) as well as 3 month (short term, mid-life onset) DR reduced the number of cells harbouring DNA damage and adipocyte size (area and perimeter) in visceral adipocytes with similar efficiency. Importantly, beneficial health markers induced by DR such as small adipocyte size and low DNA damage were maintained for at least 3 month after termination of DR, demonstrating that the previously identified 'metabolic memory' of the DR state in male mice extends to senescence markers in visceral fat.

Role of dietary amino acid balance in diet restriction-mediated lifespan extension, renoprotection, and muscle weakness in aged mice.

SummaryExtending healthy lifespan is an emerging issue in an aging society. This study was designed to identify a dietary method of extending lifespan, promoting renoprotection, and preventing muscle weakness in aged mice, with a focus on the importance of the balance between dietary essential (EAAs) and nonessential amino acids (NEAAs) on the dietary restriction (DR)‐induced antiaging effect. Groups of aged mice were fed ad libitum, a simple DR, or a DR with recovering NEAAs or EAAs. Simple DR significantly extended lifespan and ameliorated age‐related kidney injury; however, the beneficial effects of DR were canceled by recovering dietary EAA but not NEAA. Simple DR prevented the age‐dependent decrease in slow‐twitch muscle fiber function but reduced absolute fast‐twitch muscle fiber function. DR‐induced fast‐twitch muscle fiber dysfunction was improved by recovering either dietary NEAAs or EAAs. In the ad libitum‐fed and the DR plus EAA groups, the renal content of methionine, an EAA, was significantly higher, accompanied by lower renal production of hydrogen sulfide (H2S), an endogenous antioxidant. Finally, removal of methionine from the dietary EAA supplement diminished the adverse effects of dietary EAA on lifespan and kidney injury in the diet‐restricted aged mice, which were accompanied by a recovery in H2S production capacity and lower oxidative stress. These data imply that a dietary approach could combat kidney aging and prolong lifespan, while preventing muscle weakness, and suggest that renal methionine metabolism and the trans‐sulfuration pathway could be therapeutic targets for preventing kidney aging and subsequently promoting healthy aging.

Protein-Restricted Diet Is Effective in Decreasing Glycemia, HbA1c, and Cholesterol in Type 2 Diabetic Subjects by the Activation of the GCN2 Pathway

Dietary restriction increases lifespan across the evolutionary spectrum and decreases metabolic disease risk in mammals. It has been shown that amino acid restriction is sufficient to promote some of the beneficial effects of dietary restriction in rodents. This phenomenon is dependent on GCN2 (general control nonderepressible 2), a kinase activated by amino acid restriction that controls protein synthesis and stress response. Our results show that treatment of type 2 diabetic subjects on a protein restriction diet for 4 weeks exhibited a 61% reduction in fasting glucose levels and a 14% decrease in Hb1Ac. These patients had a 32% reduction in Total Cholesterol with a 33% decrease in LDL. We noticed a reduction of 4.5% of body weight, with a decrease of 11% of fat mass and maintenance of lean mass. In addition, all subjects had systemic blood pressure normalization, with a decrease of 23% in systolic pressure and 44% in diastolic pressure. In order to understand in detail the action of protein restriction we evaluated the gene expression in the subcutaneous adipose tissue of these individuals. We observed the activation of GCN2 expression (p=0.0394) and consequently the activation of ATF4 (Activating transcription factor 4) and CHOP (C/EBP homologous protein) (p=0.0360 and p=0.0011 respectively). This findings suggesting that in fact, protein restricted diet affects the GCN2 pathway in humans, modulating the energy metabolism and enabling glycemic and lipidemic control. Disclosure R.C. Ferraz: None. R.A. Beraldo: None. P. Gomes: None. M.C. Foss: None. M. Foss-Freitas: None.

Spermidine in health and disease.

Interventions that delay aging and protect from age-associated disease are slowly approaching clinical implementation. Such interventions include caloric restriction mimetics, which are defined as agents that mimic the beneficial effects of dietary restriction while limiting its detrimental effects. One such agent, the natural polyamine spermidine, has prominent cardioprotective and neuroprotective effects and stimulates anticancer immunosurveillance in rodent models. Moreover, dietary polyamine uptake correlates with reduced cardiovascular and cancer-related mortality in human epidemiological studies. Spermidine preserves mitochondrial function, exhibits anti-inflammatory properties, and prevents stem cell senescence. Mechanistically, it shares the molecular pathways engaged by other caloric restriction mimetics: It induces protein deacetylation and depends on functional autophagy. Because spermidine is already present in daily human nutrition, clinical trials aiming at increasing the uptake of this polyamine appear feasible.

The beneficial effects of dietary restriction on learning are distinct from its effects on longevity and mediated by depletion of a neuroinhibitory metabolite.

In species ranging from humans to Caenorhabditis elegans, dietary restriction (DR) grants numerous benefits, including enhanced learning. The precise mechanisms by which DR engenders benefits on processes related to learning remain poorly understood. As a result, it is unclear whether the learning benefits of DR are due to myriad improvements in mechanisms that collectively confer improved cellular health and extension of organismal lifespan or due to specific neural mechanisms. Using an associative learning paradigm in C. elegans, we investigated the effects of DR as well as manipulations of insulin, mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and autophagy pathways—processes implicated in longevity—on learning. Despite their effects on a vast number of molecular effectors, we found that the beneficial effects on learning elicited by each of these manipulations are fully dependent on depletion of kynurenic acid (KYNA), a neuroinhibitory metabolite. KYNA depletion then leads, in an N-methyl D-aspartate receptor (NMDAR)-dependent manner, to activation of a specific pair of interneurons with a critical role in learning. Thus, fluctuations in KYNA levels emerge as a previously unidentified molecular mechanism linking longevity and metabolic pathways to neural mechanisms of learning. Importantly, KYNA levels did not alter lifespan in any of the conditions tested. As such, the beneficial effects of DR on learning can be attributed to changes in a nutritionally sensitive metabolite with neuromodulatory activity rather than indirect or secondary consequences of improved health and extended longevity.

Longer life? It's all in the head

Aging Caloric restriction extends life span and helps ward off diseases of aging in model organisms and may do so in primates as well. It's not pleasant, though, so a way to mimic its effect with a drug would be more appealing. Lucanic et al. screened for such a compound in the worm Caenorhabditis elegans and found one that extended life span in a manner similar to dietary restriction. Experiments to trace the point of action of the compound indicated that it may act by limiting activity in a neuronal pathway that senses the presence of food. Thus, sensory signaling pathways might be targets for agents that could mimic beneficial effects of dietary restriction on aging and health span. Aging Cell. 10.1111/acel.12492 (2016).

Molecular mechanisms of dietary restriction in aging-insights from Caenorhabditis elegans research.

Dietary restriction (DR) is one of the most robust environmental manipulations that not only extend life span but also delay the onset of age-related diseases in almost every species examined. Caenorhabditis elegans plays an important role in aging studies due to its simple life cycle, easy genetic manipulations and highly conserved genome. Recent studies have demonstrated that the beneficial effects of DR are mediated by the highly conserved transcription factors and signaling pathways in C. elegans. Here we review recent progress in the methodology and molecular mechanisms of DR using C. elegans as a model, as well as prospects for future research.

Resveratrol Partially Suppresses Inflammatory Events but Does not Affect Stroke Onset in Stroke-Prone Spontaneously Hypertensive Rats.

Resveratrol has been shown to mimic the beneficial effects of dietary restriction (DR). We previously reported that DR delays stroke onset and extends the lifespan in Stroke-Prone Spontaneously Hypertensive rats (SHRSP). Therefore, we examined whether resveratrol mimics DR and delays stroke onset in SHRSP. Cerebrovascular endothelial cells (CVECs) from SHRSP were treated with resveratrol, and the inflammatory gene expression levels and NFκB protein levels were measured. In order to address the effects of resveratrol in vivo, SHRSP (male, 10 weeks of age) were fed an experimental diet containing several doses of resveratrol (0 - 0.05% (w/w)), after which we measured the plasma cytokine levels and examined the stroke onset and lifespan. Treatment with resveratrol (100 μM, 24 hours) in CVECs from SHRSP significantly decreased the interleukin (IL)-1β-induced monocyte chemoattractant protein-1 (MCP-1) mRNA expression levels and p50 and p65 protein levels in the nuclear fraction. When the SHRSP were fed a diet containing resveratrol for one week, the resveratrol treatment did not affect the plasma lipid and glucose levels, body weight or weight of each tissue. Resveratrol slightly, but not significantly, decreased the plasma levels of IL-1β and MCP-1 compared with that observed in the control group. In addition, resveratrol decreased the IL-1β and MCP-1 mRNA expression levels in the brain versus the control animals. However, no doses of resveratrol delayed stroke onset or extended the lifespan in SHRSP. In this study, resveratrol did not delay stroke onset in SHRSP, although it partially suppressed systemic and cerebral inflammation. These results suggest that resveratrol does not mimic the beneficial effects of DR on stroke in vivo.

Rapamycin increases mitochondrial efficiency by mtDNA-dependent reprogramming of mitochondrial metabolism in Drosophila

Downregulation of the mammalian target of rapamycin (mTOR) pathway by its inhibitor rapamycin is emerging as a potential pharmacological intervention that mimics the beneficial effects of dietary restriction. Modulation of mTOR has diverse effects on mitochondrial metabolism and biogenesis, but the role of the mitochondrial genotype in mediating these effects remains unknown. Here, we use novel mitochondrial genome replacement strains in Drosophila to test the hypothesis that genes encoded in mitochondrial DNA (mtDNA) influence the mTOR pathway. We show that rapamycin increases mitochondrial respiration and succinate dehydrogenase activity, decreases H2O2 production and generates distinct shifts in the metabolite profiles of isolated mitochondria versus whole Drosophila. These effects are disabled when divergent mitochondrial genomes from D. simulans are placed into a common nuclear background, demonstrating that the benefits of rapamycin to mitochondrial metabolism depend on genes encoded in the mtDNA. Rapamycin is able to enhance mitochondrial respiration when succinate dehydrogenase activity is blocked, suggesting that the beneficial effects of rapamycin on these two processes are independent. Overall, this study provides the first evidence for a link between mitochondrial genotype and the effects of rapamycin on mitochondrial metabolic pathways.

Enhanced Phase II Detoxification Contributes to Beneficial Effects of Dietary Restriction as Revealed by Multi-platform Metabolomics Studies

Dietary restriction (DR) has many beneficial effects, but the detailed metabolic mechanism remains largely unresolved. As diet is essentially related to metabolism, we investigated the metabolite profiles of urines from control and DR animals using NMR and LC/MS metabolomic approaches. Multivariate analysis presented distinctive metabolic profiles and marker signals from glucuronide and glycine conjugation pathways in the DR group. Broad profiling of the urine phase II metabolites with neutral loss scanning showed that levels of glucuronide and glycine conjugation metabolites were generally higher in the DR group. The up-regulation of phase II detoxification in the DR group was confirmed by mRNA and protein expression levels of uridinediphospho-glucuronosyltransferase and glycine-N-acyltransferase in actual liver tissues. Histopathology and serum biochemistry showed that DR was correlated with the beneficial effects of low levels of serum alanine transaminase and glycogen granules in liver. In addition, the Nuclear factor (erythroid-derived 2)-like 2 signaling pathway was shown to be up-regulated, providing a mechanistic clue regarding the enhanced phase II detoxification in liver tissue. Taken together, our metabolomic and biochemical studies provide a possible metabolic perspective for understanding the complex mechanism underlying the beneficial effects of DR.

Involvement of Arterial Baroreflex in the Protective Effect of Dietary Restriction Against Stroke

Dietary restriction (DR) protects against neuronal dysfunction and degeneration, and reduces the risk of ischemic stroke. This study examined the role of silent information regulator T1 (SIRT1) and arterial baroreflex in the beneficial effects of DR against stroke, using two distinct stroke models: stroke-prone spontaneously hypertensive rats (SP-SHRs) and Sprague-Dawley (SD) rats with middle cerebral artery occlusion (MCAO). Sirt1 knockout (KO) mice were used to examine the involvement of sirt1. Sinoaortic denervation was used to inactivate arterial baroreflex. Dietary restriction was defined as 40% reduction of dietary intake. Briefly, DR prolonged the life span of SP-SHRs and reduced the infarct size induced by MCAO. Dietary restriction also improved the function arterial baroreflex, decreased the release of proinflammatory cytokines, and reduced end-organ damage. The beneficial effect of DR on stroke was markedly attenuated by blunting arterial baroreflex. Lastly, the infarct area in sirt1 KO mice was significantly larger than in the wild-type mice. However, the beneficial effect of DR against ischemic injury was still apparent in sirt1 KO mice. Accordingly, arterial baroreflex, but not sirt1, is important in the protective effect of DR against stroke.

Resveratrol Rescues SIRT1-Dependent Adult Stem Cell Decline and Alleviates Progeroid Features in Laminopathy-Based Progeria

Abnormal splicing of LMNA gene or aberrant processing of prelamin A results in progeroid syndrome. Here we show that lamin A interacts with and activates SIRT1. SIRT1 exhibits reduced association with nuclear matrix (NM) and decreased deacetylase activity in the presence of progerin or prelamin A,leading to rapid depletion of adult stem cells (ASCs) in Zmpste24(-/-) mice. Resveratrol enhances the binding between SIRT1 and A-type lamins to increases its deacetylase activity. Resveratrol treatment rescues ASC decline, slows down body weight loss, improves trabecular bone structure and mineral density, and significantly extends the life span in Zmpste24(-/-) mice. Our data demonstrate lamin A as an activator of SIRT1 and provide a mechanistic explanation for the activation of SIRT1 by resveratrol. The link between conserved SIRT1 longevity pathway and progeria suggests a stem cell-based and SIRT1 pathway-dependent therapeutic strategy for progeria.