2021 Symposium on Healthy Aging
December 8, 2021
- Sailendra (Nath) Nichenametla, OFAS
Discrete effects of methionine and cysteine on sulfur amino acid restriction-induced changes in adipose metabolism
Sailendra Nichenametla1, Dwight Mattocks1, Diana Cooke1, Gene Ables1, Vishal Midya2, Virginia Malloy1, Wilfredo Mansilla3, Anna-Kate Shoveller3, John Pinto4
1Orentreich Foundation for the Advancement of Science, Cold Spring, N.Y., 2Icahn School of Medicine at Mount Sinai, New York, N.Y., 3University of Guelph, Guelph, Ontario, Canada, 4New York Medical College, Valhalla, N.Y.
Sulfur amino acid restriction (SAAR) is a dietary intervention that results in robust lifespan extension in multiple experimental models. A salient future of SAAR in laboratory animals is the remarkable improvement in adipose metabolism. Contrary to this, the effect of SAAR in humans is modest. Laboratory SAAR diet is chemically defined and formulated by decreasing the concentration of methionine (Met) and eliminating cysteine (Cys). However, due to the use of natural ingredients, the human SAAR diet cannot eliminate Cys. Although they can synthesize Cys from Met, rodents cannot meet metabolic demand as Met in the SAAR diet is low. Thus, they undergo both Met restriction (MR) and Cys restriction (CR), i.e., SAA restriction (SAAR = MR + CR). The Human SAAR diet results only in MR, as Cys level is typically unaltered. We present data that show MR and CR exert discrete effects on several SAAR phenotypes and that SAAR-induced changes in adipose metabolism are specifically due to CR.
- Christian Sell, Drexel University College of Medicine
Metabolic regulation of the senescence program through methionine restriction and mTOR inhibition
Longevity enhancing therapies such as methionine restriction, mTOR inhibition, and caloric restriction can have profound impact on lifespan and late life function, yet the mechanisms by which these interventions provide these benefits remain elusive. The laboratory is dedicated to the clinical development of these longevity enhancing therapies and to the understanding of the mechanisms involved in the benefits provided by these therapies. We have found that both methionine restriction and mTOR inhibition delay or prevent cellular senescence, a cell fate decision which produces an irreversible growth arrest, and phenotypic changes that increase inflammatory cytokine production. We have identified specific metabolic changes in the cell that link fatty acid oxidation to one carbon metabolism and histone modifications. These changes provide a mechanism allowing metabolic regulation of cell fate decisions such as entry into senescence and cell differentiation.
- Manali Potnis, Drexel University College of Medicine
An evolving role for the long non-coding RNA H19 in aging and senescence
The long non-coding RNA (lncRNA) H19 is a maternally imprinted gene transcript that, in conjunction with the neighboring Igf2 gene, is critical in controlling embryonic growth. Loss of H19 results in fetal overgrowth associated with Beckwith-Wiedemann syndrome, while elevated H19 occurs in human cancers. In the adult, H19 functions in cancer cells, where it promotes migration and is correlated with poor prognosis, and in adult stem cells where it is a key regulator of cell fate decisions during differentiation. While the function of H19 in primary somatic cells has not been defined, a reduction in the abundance of H19 has been reported during senescence in endothelial cells. Given the critical importance of H19 in cell fate decisions, it is likely that understanding the precise function of H19 in somatic cells in general and why reduced levels occur with cellular senescence will provide novel insights into both somatic cell maintenance and the senescence program. Towards this end, we examined the role of H19 in somatic cell growth using cardiac interstitial fibroblasts. Our results indicate that H19 is not only vital for somatic cell proliferation and survival, but that depletion of H19 leads to cell cycle arrest and the formation of abnormal nuclei, resulting in senescent cells. We are defining both the upstream regulators of H19 and the downstream mediators of senescence following H19 depletion. Overall, these results indicate an essential role for H19 in cell cycle progression, chromatin structure, and possibly proper mitotic division.
- Max Guo, National Institute on Aging, NIH
Aging biology research supported by the National Institute on Aging
This presentation will highlight and discuss some research and research trends on aging biology supported by the National Institute on Aging (NIA). The Division of Aging Biology at NIA promotes and supports research and training on the molecular, cellular, and physiological mechanisms underlying normal aging and age-related pathologies. It supports basic, applied and translational research on the biology of aging, and its priorities include research on (1) mechanisms of aging, (2) hallmarks and biomarkers of aging, (3) rates of aging (including lifespan and healthspan), and (4) methods to alter those to improve health at older ages. The subjects of this aging biology research include model organisms (both invertebrates and vertebrates) and humans. In addition to research, some NIA funding-related topics will be also presented.
- Zhen Dong, OFAS
Cumulative consumption of sulfur amino acid intake and incidence of diabetes
Objectives: Increasing evidence in animal models and humans suggests that diets high in sulfur-containing amino acids (SAA) could be associated a greater risk for type 2 diabetes (T2D). However, data from longitudinal human studies linking dietary SAA intake with T2D is lacking. The present study examines the association between long-term dietary intake of SAA—including total SAAs, methionine, and cysteine—and incident T2D in participants of the Framingham Heart Study (FHS).
Methods: Participants were selected from two prospective FHS cohorts: The Offspring Cohort (followed from 1992 to 2015, n=3215) and the Third Generation Cohort (followed from 2002 to 2011, n=3186). Individuals younger than 18 years, identified as diabetes patients before baseline, having missing diet or covariates data, or reporting extreme daily energy intake were excluded. Energy-adjusted intake of dietary SAAs was calculated from responses to a 131-item food frequency questionnaire. Cox proportional hazards models were used to evaluate associations between intakes of SAAs (in quintiles) and risk of T2D in each cohort. A combined patient pool from both cohorts has also been analyzed.
Results: We documented 471 incident T2D events during 9-23 years of follow-up. After adjustment for demographics, traditional risk factors, and related nutrients, higher SAA intake was associated with a higher risk of T2D. Comparing participants in the highest quintile with those in the lowest quintile of intake, adjusted hazard ratios (95% CI) were 1.93 (1.12-3.33) for total intake (P for trend = 0.04) in the Offspring Cohort, and 4.41 (1.42-13.76) (P for trend =0.04) in the Third Generation Cohort. In the combination analysis of two cohorts, adjusted hazard ratios (95% CI) were 2.01 (1.24-3.25) for total intake, 2.16 (1.35-3.46) for methionine, and 1.81 (1.13-2.91) for cysteine (P for trends <0.03).
Conclusions: Higher long-term SAA intake was associated with higher risk for T2D in humans, suggesting that dietary patterns emphasizing low SAA intake are protective against development of T2D.
- Thomas Olsen & Kathrine Vinknes, University of Oslo, Norway
Sulfur amino acids and metabolic outcomes – Preliminary data, challenges, and experiences from human clinical intervention studies
Dietary sulfur amino acid (SAA) restriction is an established animal model for increasing lifespan and improving metabolic health. Data from human studies are limited.
From 2015-2019, we performed short-term randomized controlled pilot studies in normal-weight and overweight/obese participants to assess the feasibility of sulfur amino acid restriction (SAAR) and short-term metabolic effects. Main results from the pilot trials included changes in circulating biomarkers, including FGF21, and changes in plasma and urinary concentrations of several SAA and in adipose tissue mRNA expression in line with preclinical studies.
In recent preliminary analyses on the pilot data, we assayed all sulfur metabolites (sulfurome), including less commonly assayed compounds such as inorganic sulfur compounds (sulfite, thiosulfate), organic sulfur metabolites (e.g. S-sulfocysteine), and H2S to explore the relation of specific sulfur metabolites with body composition, biomarkers, and adipocyte gene expression. Preliminary findings showed that intermediates in sulfur metabolism distal to methionine and cysteine differed between normal-weight and overweight individuals. In addition, short-term SAAR induced changes in several less commonly assayed sulfur analytes in plasma and urine.
The findings from the pilot trials will be verified and explored further in an ongoing project (ClinicalTrials.gov: NCT04701346). The study is an 8-week randomized controlled dietary intervention in which we evaluate if dietary SAAR can reduce body weight and affect resting energy metabolism, substrate oxidation, and other parameters related to metabolic health. The participants are overweight and obese men and women (sample size = 40–50), aged 18–45 years, randomized to a diet with either low or high SAA. Outcomes include changes in body weight, body composition, and resting energy expenditure and in samples of blood, urine, feces, and adipose tissue. The objective of the trial is to establish effects of SAAR with an overarching aim to translate findings from previous animal experiments to humans.
Finally, in a phase 1 dose-finding study, we are investigating the cysteine-lowering effects of the drug mesna (Uromitexan®), which increases urinary excretion of cysteine (ClinicalTrials.gov: NCT04449536). The ultimate goal of this project is to assess whether mesna can be beneficial for body weight reduction in individuals with obesity.
With these studies, we aim to establish the relevance of diet- or drug-induced SAAR in humans with regards to metabolic outcomes.
- Alessandro Bitto, University of Washington
Acarbose suppresses symptoms of mitochondrial disease in a mouse model of Leigh syndrome
Mitochondrial diseases are pathologies characterized by impairment in mitochondrial function. Mitochondrial dysfunction is also a hallmark of the aging process. Rapamycin, a drug that increases lifespan and reduces the incidence of age-related pathologies in multiple models, increases survival and reduces the impact of neurological symptoms in a mouse model lacking the complex I subunit Ndufs4. Here we show that acarbose, another drug that extends lifespan in mice, suppresses symptoms of disease and improves survival of Ndufs4-/- mice. Unlike rapamycin, acarbose rescues disease phenotypes independently of mTOR inhibition. Furthermore, rapamycin and acarbose have additive effects on clasping and maximum lifespan in Ndufs4-/- mice. Acarbose rescues mitochondrial disease independently of glycolytic flux and Sirt3 activity by potentially remodeling the microbiome. This study provides the first evidence that the microbiome may rescue severe mitochondrial disease and proof of principle that biological aging and mitochondrial disorders are driven by common mechanisms.
- Jay E. Johnson, OFAS
Dietary supplementation with compounds that produce methionine restriction-like benefits, including inhibition of insulin/IGF-1 signaling and improved healthspan
Methionine restriction (MR) dramatically extends the healthspan of several model organisms. For example, methionine-restricted rodents have less age-related pathology than control-fed littermates and are up to 45% longer-lived. Importantly, MR is feasible for humans and studies have suggested that methionine-restricted individuals may receive similar benefits to rodents. Unfortunately, long-term adherence to a methionine-restricted diet is likely to be challenging for many individuals. Prompted by this, our lab has sought to identify compounds that produce the benefits of MR, but in a normal, methionine-replete context. Here, we show that dietary supplementation with any one of four different amino acids is sufficient to produce the same beneficial metabolic effects typically observed for MR. Notably, supplemented animals are completely protected against diet-induced obesity, maintaining both normal glucose homeostasis and low levels of adiposity despite the challenge of a high-fat diet. Further, supplemented animals demonstrate the same beneficial plasma hormone changes as methionine-restricted mice, with altered circulating levels of IGF-1, FGF-21, leptin, and adiponectin. Finally, we find that similar interventions in budding yeast also mimic the ability of MR to extend the lifespan of this organism. Together, our findings reveal four novel dietary interventions that produce the same short-term healthspan benefits as MR, but in a methionine-replete context. Should future studies find that these interventions also produce MR-like benefits in humans, then supplementation with these compounds would represent an attractive alternative to maintaining a methionine-restricted diet.
- Cristal Hill, Pennington Biomedical Research Center
Linking brain FGF21 signaling to improvements in health and lifespan during dietary protein restriction
C.M. Hill1, D.C. Albarado1, L. Coco1, R. Spann1, M.S. Khan1, E. Qualls-Creekmore1, D. Burk1, S.J. Burke1, J.J. Collier1, S. Yu1, D. McDougal1, H.R. Berthoud1, H. Münzberg1, A. Bartke2, C.D. Morrison1
1Pennington Biomedical Research Center, Baton Rouge, La.; 2Depts of Internal Medicine & Physiology, Southern Illinois University School of Medicine, Springfield, Ill.
Dietary protein restriction (DPR), without reducing caloric intake, improves metabolic health and extends lifespan in various organisms. In addition, amino acid restriction, including methionine restriction (MR) and reducing branched chain amino acids (BCAA), also produces favorable outcomes on health and lifespan. Recent work demonstrates that DPR protects against obesity, increases energy expenditure, and improves glucose homeostasis, and this effect is largely mediated by the metabolic hormone FGF21. Other studies report that consistent high levels of FGF21 extend lifespan, as observed in transgenic mice overexpressing FGF21. DPR creates a unique physiological approach to define the underlying mechanisms that contribute to these beneficial effects. The goal of this work is to connect the effects of protein intake and FGF21 signaling on metabolism, feeding behavior, and longevity, and experiments in our lab have specifically focused on identifying the site of action and potential mechanisms through which DPR-induced FGF21 signaling improves metabolism and protects against aging. Our collective data demonstrate that FGF21 signaling in the brain is required for DPR-induced improvements in metabolism and that FGF21 is required for DPR to defend against age-related metabolic and physical impairment, and in turn, extend lifespan. This work is funded by the National Institutes of Health (NIH) F32DK115137, R01DK105032, R01DK121370, S10OD023703, R21AG062985.