Healthspan Extension Research Articles

The ageing epigenome and itsrejuvenation.

Ageing is characterized by the functional decline of tissues and organs and the increased risk of ageing-associated disorders. Several 'rejuvenating' interventions have been proposed to delay ageing and the onset of age-associated decline and disease to extend healthspan and lifespan. These interventions include metabolic manipulation, partial reprogramming, heterochronic parabiosis, pharmaceutical administration and senescent cell ablation. As the ageing process is associated with altered epigenetic mechanisms of gene regulation, such as DNA methylation, histone modification and chromatin remodelling, and non-coding RNAs, the manipulation of these mechanisms is central to the effectiveness of age-delaying interventions. This Review discusses the epigenetic changes that occur during ageing and the rapidly increasing knowledge of how these epigenetic mechanisms have an effect on healthspan and lifespan extension, and outlines questions to guide future research on interventions to rejuvenate the epigenome and delay ageing processes.

Nanodelivery of phytobioactive compounds for treating aging-associated disorders.

Aging population presents a major challenge for many countries in the world and has made the development of efficient means for healthspan extension a priority task for researchers and clinicians worldwide. Anti-aging properties including antioxidant, anti-inflammatory, anti-tumor, and cardioprotective activities have been reported for various phytobioactive compounds (PBCs) including resveratrol, quercetin, curcumin, catechin, etc. However, the therapeutic potential of orally administered PBCs is limited by their poor stability, bioavailability, and solubility in the gastrointestinal tract. Recently, innovative nanotechnology-based approaches have been developed to improve the bioactivity of PBCs and enhance their potential in preventing and/or treating age-associated disorders, primarily those caused by aging-related chronic inflammation. PBC-loaded nanoparticles designed for oral administration provide many benefits over conventional formulations, including enhanced stability and solubility, prolonged half-life, improved epithelium permeability and bioavailability, enhanced tissue targeting, and minimized side effects. The present review summarizes recent advances in this rapidly developing research area.

A cell-based assay system for activators of the environmental cell stress response

Improved health span and lifespan extension in a wide phylogenetic range of species is associated with the induction of the environmental cell stress response through a signalling pathway regulated by the transcription factor Nrf2. Phytochemicals which stimulate this response may form part of therapeutic interventions which stimulate endogenous cytoprotective mechanisms, thereby delaying the onset of age-related diseases and promoting healthy ageing in humans. In order to identify compounds that activate the Nrf2 pathway, a cell-based reporter system was established in HepG2 cells using a luciferase reporter gene under the control of the Nqo1 promoter. Sulforaphane, an isothiocyanate derived from cruciferous vegetables and a known activator of the Nrf2 pathway, was used to validate the reporter system. The transfected cell line HepG2 C1 was subsequently used to screen natural product libraries. Five compounds were identified as activating the bioluminescent reporter by greater than 5-fold. The two most potent compounds, MBC20 and MBC37, were further characterised and shown to stimulate endogenous cytoprotective gene and protein expression. The bioluminescent reporter system will allow rapid, in vitro identification of novel compounds that have the potential to improve health span through activation of the environmental stress response.

Development of an IGF1R longevity variant mouse line using CRISPR/Cas9 genome editing.

An insulin-like growth factor-1 receptor (IGF1R) variant in exon 6 (Arg-407-His) in Ashkenazi Jewish centenarians was previously found to be associated with reduced IGF1R activity. To further study this longevity associated IGF1R variant, we generated a novel mouse line carrying the R407H variant in exon 6 of the Igf1r gene by employing CRISPR/Cas9 genome editing technology. Here, we show that the Igf1r gene can be edited in mouse embryos by zygotic electroporation of Cas9 protein and a single-guide RNAs together with a single stranded oligonucleotide donor containing the desired key nucleotide changes at the Igf1r locus. Sequence analysis of F0 and F1 mice following targeted editing demonstrated the robustness of this approach in mice using CRISPR/Cas9 directed homologous recombination (HDR). Western blot analysis indicates that mice heterozygous for the variant have a significant decrease in IGF1R phosphorylation in various tissues, including skeletal muscle, compared to wildtype. In addition, depletion of IGF1R signaling specifically in skeletal muscle of progeroid Ercc1 -/Δ mice resulted in extended health span and median lifespan providing the rationale for long term lifespan studies in Igf1r hR407H variant mice. This mouse line will be a valuable genetic tool to help determine the impact of IGF1R signaling on aging and longevity. The CRISPR editing approach represents a prototype for generating additional longevity associated gene variant mouse lines to study relevance to human exceptional longevity.

PROTACs are effective in addressing the platelet toxicity associated with BCL-XL inhibitors.

BCL-XL is an anti-apoptotic protein that plays an important role in tumorigenesis, metastasis, and intrinsic or therapy-induced cancer drug resistance. More recently, BCL-XL has also been identified as a key survival factor in senescent cells. Accumulation of senescent cells has been indicated as a causal factor of aging and many age-related diseases and contributes to tumor relapse and metastasis. Thus, inhibition of BCL-XL is an attractive strategy for the treatment of cancer and extension of healthspan. However, development of BCL-XL inhibitors such as navitoclax for clinical use has been challenging because human platelets depend on BCL-XL for survival. In this review, the authors discuss how BCL-XL-targeted proteolysis targeting chimeras (PROTACs) afford a novel approach to mitigate the on-target thrombocytopenia associated with BCL-XL inhibition. The authors summarize the progress in the development of BCL-XL PROTACs. The authors highlight the in vitro and in vivo data supporting that by hijacking the ubiquitin protein ligase (E3) that are poorly expressed in human platelets, BCL-XL PROTACs can significantly improve the therapeutic window compared to conventional BCL-XL inhibitors. These findings demonstrated the potentially broad utility of PROTAC technology to achieve tissue selectivity through recruiting differentially expressed E3 ligases and to reduce on-target toxicity.

The Use of Metformin to Increase the Human Healthspan.

Metformin is a safe, effective and useful drug for glucose management in patients with diabetes. However in recent years, more attention has been paid to the possibility of using metformin as an anti-aging drug. It was shown to significantly increase the lifespan in some model organisms and delay the onset of age-associated declines. The current review summarizes advances in clinical research on the potential role of metformin in the field of lifespan and healthspan extension. Growing amounts of evidence from clinical trials suggest that metformin can effectively reduce the risk of many age-related diseases and conditions, including cardiometabolic disorders, neurodegeneration, chronic inflammation and frailty. Metformin also holds promise as a drug that could be repurposed for chemoprevention or adjuvant therapy for certain types of cancer. Moreover, metformin induces autophagy by activation of AMPK and can thus be potentially used to promote heathspan by hormesis-like mechanisms. Although long-term intake of metformin is associated with low risk of adverse events, well-designed clinical trials are still required to uncover the potential use of this drug as a geroprotector.

Antiaging, Stress Resistance, and Neuroprotective Efficacies of Cleistocalyx nervosum var. paniala Fruit Extracts Using Caenorhabditis elegans Model.

Plant parts and their bioactive compounds are widely used by mankind for their health benefits. Cleistocalyx nervosum var. paniala is one berry fruit, native to Thailand, known to exhibit various health benefits in vitro. The present study was focused on analyzing the antiaging, stress resistance, and neuroprotective effects of C. nervosum in model system Caenorhabditis elegans using physiological assays, fluorescent imaging, and qPCR analysis. The results suggest that the fruit extract was able to significantly extend the median and maximum lifespan of the nematode. It could also extend the healthspan by reducing the accumulation of the “age pigment” lipofuscin, inside the nematode along with regulating the expression of col-19, egl-8, egl-30, dgk-1, and goa-1 genes. Further, the extracts upregulated the expression of daf-16 while downregulating the expression of daf-2 and age-1 in wild-type nematodes. Interestingly, it could extend the lifespan in DAF-16 mutants suggesting that the extension of lifespan and healthspan was dependent and independent of DAF-16-mediated pathway. The fruit extract was also observed to reduce the level of Reactive Oxygen Species (ROS) inside the nematode during oxidative stress. The qPCR analysis suggests the involvement of skn-1 and sir-2.1 in initiating stress resistance by activating the antioxidant mechanism. Additionally, the fruit could also elicit neuroprotection as it could extend the median and maximum lifespan of transgenic strain integrated with Aβ. SKN-1 could play a pivotal role in establishing the antiaging, stress resistance, and neuroprotective effect of C. nervosum. Overall, C. nervosum can be used as a nutraceutical in the food industry which could offer potential health benefits.

LEVERAGING DRUG-DRUG INTERACTIONS FOR PHARMACOLOGICAL EXTENSION OF HEALTHY LIFESPAN

Traditional approaches aimed at delaying or preventing age-dependent diseases view each disease as a distinct entity, resulting from separate pathophysiological chains of events. However, it is becoming increasing clear that even in adult animals there remains significant plasticity in terms of ageing trajectories and lifespan, suggesting that targeting ageing processes directly may be a promising alternative strategy. However, to date effects of even the most efficacious pharmacological interventions are smaller than those of ageing mutations, even when targeting the same ageing pathways. Interestingly, it has been shown that simultaneously targeting multiple ageing pathways can result in lifespan benefits that are synergistic (more than additive). We have recently shown that dramatic lifespan and healthspan extension can also be archived by leveraging interactions between drugs targeting distinct subsets of the gene-regulatory network controlling ageing of C. elegans. These interventions were highly efficacious, even when animals were treated only as adults.

GABA receptors differentially regulate life span and health span in C. elegans through distinct downstream mechanisms.

GABA, a prominent inhibitory neurotransmitter, is best known to regulate neuronal functions in the nervous system. However, much less is known about the role of GABA signaling in other physiological processes. Interestingly, recent work showed that GABA signaling can regulate life span via a metabotropic GABAB receptor in Caenorhabditis elegans. However, the role of other types of GABA receptors in life span has not been clearly defined. It is also unclear whether GABA signaling regulates health span. Here, using C. elegans as a model, we systematically interrogated the role of various GABA receptors in both life span and health span. We find that mutations in four different GABA receptors extend health span by promoting resistance to stress and pathogen infection and that two such receptor mutants also show extended life span. Different GABA receptors engage distinct transcriptional factors to regulate life span and health span, and even the same receptor regulates life span and health span via different transcription factors. Our results uncover a novel, profound role of GABA signaling in aging in C. elegans, which is mediated by different GABA receptors coupled to distinct downstream effectors.

Fine-Tuning of PGC1α Expression Regulates Cardiac Function and Longevity.

PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1α) represents an attractive target interfering bioenergetics and mitochondrial homeostasis, yet multiple attempts have failed to upregulate PGC1α expression as a therapy, for instance, causing cardiomyopathy. To determine whether a fine-tuning of PGC1α expression is essential for cardiac homeostasis in a context-dependent manner. Moderate cardiac-specific PGC1α overexpression through a ROSA26 locus knock-in strategy was utilized in WT (wild type) mice and in G3Terc-/- (third generation of telomerase deficient; hereafter as G3) mouse model, respectively. Ultrastructure, mitochondrial stress, echocardiographic, and a variety of biological approaches were applied to assess mitochondrial physiology and cardiac function. While WT mice showed a relatively consistent PGC1α expression from 3 to 12 months old, age-matched G3 mice exhibited declined PGC1α expression and compromised mitochondrial function. Cardiac-specific overexpression of PGC1α (PGC1αOE) promoted mitochondrial and cardiac function in 3-month-old WT mice but accelerated cardiac aging and significantly shortened life span in 12-month-old WT mice because of increased mitochondrial damage and reactive oxygen species insult. In contrast, cardiac-specific PGC1α knock in in G3 (G3 PGC1αOE) mice restored mitochondrial homeostasis and attenuated senescence-associated secretory phenotypes, thereby preserving cardiac performance with age and extending health span. Mechanistically, age-dependent defect in mitophagy is associated with accumulation of damaged mitochondria that leads to cardiac impairment and premature death in 12-month-old WT PGC1αOE mice. In the context of telomere dysfunction, PGC1α induction replenished energy supply through restoring the compromised mitochondrial biogenesis and thus is beneficial to old G3 heart. Fine-tuning the expression of PGC1α is crucial for the cardiac homeostasis because the balance between mitochondrial biogenesis and clearance is vital for regulating mitochondrial function and homeostasis. These results reinforce the importance of carefully evaluating the PGC1α-boosting strategies in a context-dependent manner to facilitate clinical translation of novel cardioprotective therapies.

Health Benefits of Nut Consumption in Middle-Aged and Elderly Population.

Aging is considered the major risk factor for most chronic disorders. Oxidative stress and chronic inflammation are two major contributors for cellular senescence, downregulation of stress response pathways with a decrease of protective cellular activity and accumulation of cellular damage, leading in time to age-related diseases. This review investigated the most recent clinical trials and cohort studies published in the last ten years, which presented the influence of tree nut and peanut antioxidant diets in preventing or delaying age-related diseases in middle-aged and elderly subjects (≥55 years old). Tree nut and peanut ingestion has the possibility to influence blood lipid count, biochemical and anthropometric parameters, endothelial function and inflammatory biomarkers, thereby positively affecting cardiometabolic morbidity and mortality, cancers, and cognitive disorders, mainly through the nuts’ healthy lipid profile and antioxidant and anti-inflammatory mechanisms of actions. Clinical evidence and scientific findings demonstrate the importance of diets characterized by a high intake of nuts and emphasize their potential in preventing age-related diseases, validating the addition of tree nuts and peanuts in the diet of older adults. Therefore, increased consumption of bioactive antioxidant compounds from nuts clearly impacts many risk factors related to aging and can extend health span and lifespan.

Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice.

The gut microbiome is emerging as a key regulator of several metabolic, immune and neuroendocrine pathways1,2. Gut microbiome deregulation has been implicated in major conditions such as obesity, type 2 diabetes, cardiovascular disease, non-alcoholic fatty acid liver disease and cancer3-6, but its precise role in aging remains to be elucidated. Here, we find that two different mouse models of progeria are characterized by intestinal dysbiosis with alterations that include an increase in the abundance of Proteobacteria and Cyanobacteria, and a decrease in the abundance of Verrucomicrobia. Consistent with these findings, we found that human progeria patients also display intestinal dysbiosis and that long-lived humans (that is, centenarians) exhibit a substantial increase in Verrucomicrobia and a reduction in Proteobacteria. Fecal microbiota transplantation from wild-type mice enhanced healthspan and lifespan in both progeroid mouse models, and transplantation with the verrucomicrobia Akkermansia muciniphila was sufficient to exert beneficial effects. Moreover, metabolomic analysis of ileal content points to the restoration of secondary bile acids as a possible mechanism for the beneficial effects of reestablishing a healthy microbiome. Our results demonstrate that correction of the accelerated aging-associated intestinal dysbiosis is beneficial, suggesting the existence of a link between aging and the gut microbiota that provides a rationale for microbiome-based interventions against age-related diseases.

Exercise-Induced Mitohormesis for the Maintenance of Skeletal Muscle and Healthspan Extension.

Oxidative damage is one mechanism linking aging with chronic diseases including the progressive loss of skeletal muscle mass and function called sarcopenia. Thus, mitigating oxidative damage is a potential avenue to prevent or delay the onset of chronic disease and/or extend healthspan. Mitochondrial hormesis (mitohormesis) occurs when acute exposure to stress stimulates adaptive mitochondrial responses that improve mitochondrial function and resistance to stress. For example, an acute oxidative stress via mitochondrial superoxide production stimulates the activation of endogenous antioxidant gene transcription regulated by the redox sensitive transcription factor Nrf2, resulting in an adaptive hormetic response. In addition, acute stresses such as aerobic exercise stimulate the expansion of skeletal muscle mitochondria (i.e., mitochondrial biogenesis), constituting a mitohormetic response that protects from sarcopenia through a variety of mechanisms. This review summarized the effects of age-related declines in mitochondrial and redox homeostasis on skeletal muscle protein homeostasis and highlights the mitohormetic mechanisms by which aerobic exercise mitigates these age-related declines and maintains function. We discussed the potential efficacy of targeting the Nrf2 signaling pathway, which partially mediates adaptation to aerobic exercise, to restore mitochondrial and skeletal muscle function. Finally, we highlight knowledge gaps related to improving redox signaling and make recommendations for future research.

Superior Aerobic Capacity and Indices of Skeletal Muscle Morphology in Chronically Trained Master Endurance Athletes Compared With Untrained Older Adults

The study aim was to comprehensively assess physiological function and muscle morphology in chronically trained older individuals against untrained young and older individuals. In a cross-sectional design, 15 young untrained controls (YC) (20 ± 2.7 years, 78.9 ± 13.3 kg), 12 untrained older controls (OC) (69.8 ± 4.1 years, 77.5 ± 14.2 kg), and 14 endurance-trained master athletes (MA) (67.1 ± 4.1 years, 68.7 ± 6.5 kg) underwent assessments of body composition, aerobic capacity, strength, muscle architecture, and fiber-type morphology. Skeletal muscle index was lower and body fat greater in OC versus MA. Estimated VO2max (mL·kg-1·minute-1) was similar between MA and YC, but lower in OC. Isometric leg strength normalized to fat-free mass was similar between groups, whereas normalized isometric arm strength was greater in YC than MA. Myosin heavy chain (MHC) I fiber area was greater in MA than OC, while MHC II fiber area was greater in YC than OC. MHC II fiber myonuclear domain size was greater in YC than OC and MA, whereas MA had greater MHC I and MHC II fiber capillarization than OC and YC. Satellite cell content was similar between groups. Chronic endurance training enhances indices of muscle morphology and improves body composition and aerobic capacity in older age, with potentially important implications for healthspan extension.

The role of sphingolipid metabolism in lifespan and healthspan extension in C. elegans

Multiple advancements in research have led to a better understanding of the aging process. However, many metabolic pathways that promote healthy aging are still unknown. Here, we investigate the bioactive sphingolipid metabolism pathway and its roles in regulating lifespan and healthspan, which is the average period of one's life in good health. Sphingolipids are involved in cellular signaling and known to promote cell proliferation, secretion, stress response and survival. The sphingolipid pathway is composed of sphingomyelin, ceramide, sphingosine and sphingosine‐1‐phosphate (S1P). Ceramide synthases (CER synthases) mediate the conversion of ceramide to sphingosine while sphingosine kinase (SPHK) converts sphingosine to S1P. Using C. elegans, we previously found that mutations in sphk‐1/SPHK and hyl‐2/CER synthase result in decreased lifespan, suggesting that sphingolipids play a role in lifespan extension. However, it is unknown whether the sphingolipid genes act in known cellular pathways that mediate aging. Therefore, we tested the genetic interactions between sphingolipid enzymes and known models of aging, including the insulin like signaling (ILS) pathway that has been linked to lifespan extension. For this, lifespan analyses were performed on daf‐16/FOXO, which has a shortened lifespan phenotype, coupled with knockdown of sphingolipid metabolism genes. DAF‐16 is a downstream transcription factor target of DAF‐2/insulin‐like growth factor receptor and has important roles in mediating the gene expression of stress response. We observed that daf‐16 is epistatic to sphingolipid mutants for lifespan phenotypes, as indicated by similar short lifespan phenotypes of double knockout of daf‐16;hyl‐2 and daf‐16;sphk‐1compared to mutants with a single knockout of daf‐16. Thus, sphingolipids may act upstream of DAF‐16 to mediate stress response genes and lifespan. Future experiments will analyze transcriptional reporters for DAF‐16, and known stress response genes SOD‐3/superoxide dismutase, to determine whether cellular stress response mechanisms occurs normally in hyl‐2 and sphk‐1mutants under induced oxidative stress. An analysis of stress response will further enhance our understanding of the interaction between sphingolipids and known pathways that promote lifespan and healthspan.Support or Funding InformationResearch reported in this publication was supported by the National Institute On Aging of the National Institutes of Health under Award Number R15AG052933.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Epimedium flavonoids mitigate proteotoxicity and extend healthspan via DAF-16 inC. elegans

Objective: Epimedium flavonoids (EF), the raw extract of medicinal herb Epimedium, have been shown to have broad beneficial effects in the elderly including those with neurodegeneration. The goal of this study is to investigate whether EF is protective against proteotoxicity and whether it extends healthspan in C. elegans.Methods: Animals were treated with EF supplemented in the growth medium. Two C. elegans models of human proteotoxic disease, CL4176 expressing an aggregated amyloid-[Formula: see text] (1–42) peptide (A[Formula: see text]1–42) and AM140 expressing a polyglutamine (polyQ) protein, were exploited to test the anti-proteotoxicity of EF. Proteotoxicity-induced paralysis in CL4176 and AM140 was evaluated. Lifespan, stress resistance, and locomotion were tested in wild-type N2 C. elegans. Lifespan assays were also performed in CF1038, a daf-16 null mutant strain. DAF-16 nuclear translocation was analyzed in TJ356, a strain expressing a functional DAF-16::GFP fusion protein. The mRNA levels of downstream targets of DAF-16 were measured by qPCR.Results: EF significantly reduced A[Formula: see text]1–42- and polyQ-induced paralysis in CL4176 and AM140, indicating the anti-proteotoxic potency of EF. EF significantly extended the lifespan and promoted stress resistance and locomotion in N2, demonstrating a healthspan extension effect of EF. DAF-16 nuclear localization and its downstream targets, sod-3 and hsp-16.2 mRNA levels, were significantly elevated with EF. EF did not increase the lifespan of daf-16 null mutant CF1038, revealing a DAF-16-dependent mechanism of EF effect on lifespan.Conclusion: We found that EF, a natural extract from a widely used medicinal herb Epimedium, protects against proteotoxicity and extends the healthspan via DAF-16 in C. elegans. Our work may provide molecular insights into the clinical benefits of EF and Epimedium.

Senotherapeutics: emerging strategy for healthy aging and age-related disease

Cellular senescence (CS) is one of hallmarks of aging and accumulation of senescent cells (SCs) with age contributes to tissue or organismal aging, as well as the pathophysiologies of diverse age-related diseases (ARDs). Genetic ablation of SCs in tissues lengthened health span and reduced the risk of age-related pathologies in a mouse model, suggesting a direct link between SCs, longevity, and ARDs. Therefore, senotherapeutics, medicines targeting SCs, might be an emerging strategy for the extension of health span, and prevention or treatment of ARDs. Senotherapeutics are classified as senolytics which kills SCs selectively; senomorphics which modulate functions and morphology of SCs to those of young cells, or delays the progression of young cells to SCs in tissues; and immune-system mediators of the clearance of SCs. Some senolytics and senomorphics have been proven to markedly prevent or treat ARDs in animal models. This review will present the current status of the development of senotherapeutics, in relation to aging itself and ARDs. Finally, future directions and opportunities for senotherapeutics use will discussed. This knowledge will provide information that can be used to develop novel senotherapeutics for health span and ARDs.

Health Benefits of Anti-aging Drugs.

Aging, as a physiological process mediated by numerous regulatory pathways and transcription factors, is manifested by continuous progressive functional decline and increasing risk of chronic diseases. There is an increasing interest to identify pharmacological agents for treatment and prevention of age-related disease in humans. Animal models play an important role in identification and testing of anti-aging compounds; this step is crucial before the drug will enter human clinical trial or will be introduced to human medicine. One of the main goals of animal studies is better understanding of mechanistic targets, therapeutic implications and side-effects of the drug, which may be later translated into humans. In this chapter, we summarized the effects of different drugs reported to extend the lifespan in model organisms from round worms to rodents. Resveratrol, rapamycin, metformin and aspirin, showing effectiveness in model organism life- and healthspan extension mainly target the master regulators of aging such as mTOR, FOXO and PGC1α, affecting autophagy, inflammation and oxidative stress. In humans, these drugs were demonstrated to reduce inflammation, prevent CVD, and slow down the functional decline in certain organs. Additionally, potential anti-aging pharmacologic agents inhibit cancerogenesis, interfering with certain aspects of cell metabolism, proliferation, angioneogenesis and apoptosis.

Genome-Wide Analyses for Lifespan and Healthspan in <i>D. Melanogaster</i> Reveal Decima as a Regulator of Insulin-Like Peptide Production

Dietary restriction (DR) extends lifespan and delays age-related diseases across species. An underlying assumption in the aging field is that DR extends both lifespan and healthspan through similar mechanisms, but this has not been rigorously tested in different genetic backgrounds. Furthermore, nutrient response genes responsible for lifespan or healthspan extension remain underexplored in natural populations. To address this, we measured nutrient-dependent changes in lifespan and age-related climbing ability, a measure of healthspan, in the DGRP strains. DR generally extended lifespan and delayed decline in climbing ability, but there was a lack of correlation between these traits across individual strains. We then identified and validated decima as a lifespan determinant and Daedalus for climbing. We found that decima regulates insulin-like peptide transcription in the GABA receptor neurons through sNPF signaling. Modulating these genes produced independent effects on lifespan and climbing, which suggests that these age-related traits are regulated through distinct mechanisms.

Growth Hormone Deficiency: Health and Longevity.

The important role of GH in the control of mammalian longevity was first deduced from extended longevity of mice with genetic GH deficiency (GHD) or GH resistance. Mice with isolated GHD (IGHD) due to GHRH or GHRH receptor mutations, combined deficiency of GH, prolactin, and TSH, or global deletion of GH receptors live longer than do their normal siblings. They also exhibit multiple features of delayed and/or slower aging, accompanied by extension of healthspan. The unexpected, remarkable longevity benefit of severe endocrine defects in these animals presumably represents evolutionarily conserved trade-offs among aging, growth, maturation, fecundity, and the underlying anabolic processes. Importantly, the negative association of GH signaling with longevity extends to other mammalian species, apparently including humans. Data obtained in humans with IGHD type 1B, owing to a mutation of the GHRH receptor gene, in the Itabaianinha County, Brazil, provide a unique opportunity to study the impact of severe reduction in GH signaling on age-related characteristics, health, and functionality. Individuals with IGHD are characterized by proportional short stature, doll facies, high-pitched voices, and central obesity. They have delayed puberty but are fertile and generally healthy. Moreover, these IGHD individuals are partially protected from cancer and some of the common effects of aging and can attain extreme longevity, 103 years of age in one case. We think that low, but detectable, residual GH secretion combined with life-long reduction of circulating IGF-1 and with some tissue levels of IGF-1 and/or IGF-2 preserved may account for the normal longevity and apparent extension of healthspan in these individuals.