scholarly journals Cross-species functional modules link proteostasis to human normal aging

2018 ◽  
Author(s):  
Andrea Komljenovic ◽  
Hao Li ◽  
Vincenzo Sorrentino ◽  
Zoltán Kutalik ◽  
Johan Auwerx ◽  
...  
Keyword(s):  
Caloric Restriction ◽  
Healthy Aging ◽  
Protein Quality ◽  
Normal Aging ◽  
Model Organisms ◽  
List Type ◽  
Genome Wide Association Studies ◽  
Functional Modules ◽  
Age Related ◽  
Evolutionarily Conserved

AbstractThe evolutionarily conserved nature of the few well-known anti-aging interventions that affect lifespan, such as caloric restriction, suggests that aging-related research in model organisms is directly relevant to human aging. Since human lifespan is a complex trait, a systems-level approach will contribute to a more comprehensive understanding of the underlying aging landscape. Here, we integrate evolutionary and functional information of normal aging across human and model organisms at three levels: gene-level, process-level, and network-level. We identify evolutionarily conserved modules of normal aging across diverse taxa, and importantly, we show that proteostasis involvement is conserved in healthy aging. Additionally, we find that mechanisms related to protein quality control network are enriched in 22 age-related genome-wide association studies (GWAS) and are associated to caloric restriction. These results demonstrate that a systems-level approach, combined with evolutionary conservation, allows the detection of candidate aging genes and pathways relevant to human normal aging.HighlightsNormal aging is evolutionarily conserved at the module level.Core pathways in healthy aging are related to mechanisms of protein quality networkThe evolutionarily conserved pathways of healthy aging react to caloric restriction.Our integrative approach identifies evolutionarily conserved functional modules and showed enrichment in several age-related GWAS studies.

scholarly journals Resveratrol: A Sirtuin Activator and The Fountain of Youth

2015 ◽  
Vol 7 (1) ◽  
pp. 1 ◽  
Author(s):  
Anna Meiliana ◽  
Nurrani Mustika Dewi ◽  
Andi Wijaya
Keyword(s):  
Caloric Restriction ◽  
Healthy Aging ◽  
Myocardial Infarct ◽  
Functional Decline ◽  
Steady Increase ◽  
Healthy Human ◽  
Aging Research ◽  
Human Lifespan ◽  
Age Related ◽  
Fountain Of Youth

BACKGROUND: An organism’s lifespan is inevitably accompanied by the aging process, which involves functional decline, a steady increase of a plethora of chronic diseases, and ultimately death. Thus, it has been an ongoing dream of mankind to improve healthspan and extend life.CONTENT: There are only a few proposed aging interventions: caloric restriction, exercise, and the use of low-molecular-weight compounds, including spermidine, metformin, resveratrol, and rapamycin. Resveratrol, a constituent of red wine, has long been suspected to have cardioprotective effects. Interest in this compound has been renewed in recent years, first from its identification as a chemopreventive agent for skin cancer, and subsequently from reports that it activates sirtuin deacetylases and extends the lifespans of lower organisms. Resveratrol have been shown to prevent and reduce the severity of age-related diseases such as atherosclerosis, stroke, myocardial infarct, diabetes, neurodegenerative diseases, osteoarthritis, tumors and metabolic syndrome, along with their ability to extend lifespan.SUMMARY: The purpose of aging research is the identification of interventions that may avoid or ameliorate the ravages of time. In other words, the quest is for healthy aging, where improved longevity is coupled to a corresponding healthspan extension. It is only by extending the healthy human lifespan that we will truly meet the premise of the Roman poet Cicero: “No one is so old as to think that he may not live a year.”KEYWORDS: aging, caloric restriction, mimetic, healthspan, sirtuin activator

scholarly journals Serum Factors Mediate the Bioenergetic Benefits of Exercise Training and Caloric Restriction

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 127-127
Author(s):  
Jenny Gonzalez-Armenta ◽  
Barbara Nicklas ◽  
Anthony Molina
Keyword(s):  
Resistance Training ◽  
Caloric Restriction ◽  
Mitochondrial Function ◽  
Healthy Aging ◽  
Post Intervention ◽  
Respiratory Capacity ◽  
Serum Factors ◽  
Exercise Interventions ◽  
Age Related ◽  
Diet And Exercise

Abstract Diet and exercise interventions have been shown to improve age-related decline in mitochondrial function. While the systemic benefits of diet and exercise are apparent, the mechanisms underlying these changes are not known. Our lab and others have used blood-based bioenergetic profiling to demonstrate that systemic bioenergetic capacity is related to many aspects of healthy aging, including: gait speed, grip strength, and inflammation. This work suggests a potential role for circulating factors in mediating systemic mitochondrial function. In this study, we developed a high-throughput respirometry assay to examine the effects of circulating factors on mitochondrial function of myoblasts in vitro. We used serum from older, overweight and obese adults who participated in a clinical trial comparing resistance training (RT) and resistance training plus caloric restriction (RT+CR). When combined, both interventions significantly increased serum-mediated basal (42.08 to 50.14 pmol/min, p=0.004), ATP-linked (35.57 to 42.37 pmol/min, p=0.006), and maximal respiration (132.30 to 150.00 pmol/min, p=0.02). With RT, we found significantly increased basal (40.80 to 53.85 pmol/min, p=0.01) and ATP-linked respiration (34.36 to 46.39 pmol/min, p=0.007) and trends for increased maximal respiration (130.09 to 153.24 pmol/min, p=0.10) and spare respiratory capacity (89.30 to 101.38 pmol/min, p=0.07). With RT+CR, there were trends for increased maximal respiration (134.32 to 147.06 pmol/min, p=0.10) and spare respiratory capacity (91.06 to 100.41 pmol/min, p=0.11). Additionally, we found that post-intervention serum-mediated basal and ATP-linked respiration were significantly and positively correlated with physical ability, as reported by SPPB score. Future studies will focus on identifying circulating factors responsible for these changes.

scholarly journals Endoplasmic reticulum-associated SKN-1A/Nrf1 mediates a cytoplasmic unfolded protein response and promotes longevity

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Nicolas J Lehrbach ◽  
Gary Ruvkun
Keyword(s):  
Amyloid Beta ◽  
Healthy Aging ◽  
Protein Quality ◽  
Cellular Protein ◽  
Amyloid Beta Peptide ◽  
Proteasome Subunit ◽  
Unfolded Protein ◽  
Age Related ◽  
Beta Peptide ◽  
Subunit Expression

Unfolded protein responses (UPRs) safeguard cellular function during proteotoxic stress and aging. In a previous paper (Lehrbach and Ruvkun, 2016) we showed that the ER-associated SKN-1A/Nrf1 transcription factor activates proteasome subunit expression in response to proteasome dysfunction, but it was not established whether SKN-1A/Nrf1 adjusts proteasome capacity in response to other proteotoxic insults. Here, we reveal that misfolded endogenous proteins and the human amyloid beta peptide trigger activation of proteasome subunit expression by SKN-1A/Nrf1. SKN-1A activation is protective against age-dependent defects caused by accumulation of misfolded and aggregation-prone proteins. In a C. elegans Alzheimer’s disease model, SKN-1A/Nrf1 slows accumulation of the amyloid beta peptide and delays adult-onset cellular dysfunction. Our results indicate that SKN-1A surveys cellular protein folding and adjusts proteasome capacity to meet the demands of protein quality control pathways, revealing a new arm of the cytosolic UPR. This regulatory axis is critical for healthy aging and may be a target for therapeutic modulation of human aging and age-related disease.

scholarly journals Terpenoids as Potential Geroprotectors

Antioxidants ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 529
Author(s):  
Ekaterina Proshkina ◽  
Sergey Plyusnin ◽  
Tatyana Babak ◽  
Ekaterina Lashmanova ◽  
Faniya Maganova ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Stress Resistance ◽  
Biological Effects ◽  
Plant Secondary Metabolites ◽  
Mechanisms Of Action ◽  
Model Organisms ◽  
Age Related ◽  
Evolutionarily Conserved ◽  
Low Toxicity

Terpenes and terpenoids are the largest groups of plant secondary metabolites. However, unlike polyphenols, they are rarely associated with geroprotective properties. Here we evaluated the conformity of the biological effects of terpenoids with the criteria of geroprotectors, including primary criteria (lifespan-extending effects in model organisms, improvement of aging biomarkers, low toxicity, minimal adverse effects, improvement of the quality of life) and secondary criteria (evolutionarily conserved mechanisms of action, reproducibility of the effects on different models, prevention of age-associated diseases, increasing of stress-resistance). The number of substances that demonstrate the greatest compliance with both primary and secondary criteria of geroprotectors were found among different classes of terpenoids. Thus, terpenoids are an underestimated source of potential geroprotectors that can effectively influence the mechanisms of aging and age-related diseases.

scholarly journals Translational Geroscience: Human Models of Healthy Aging and Longevity

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 300-300
Author(s):  
Sofiya Milman
Keyword(s):  
Healthy Aging ◽  
Model Organisms ◽  
Antagonistic Pleiotropy ◽  
Older Individuals ◽  
Ideal Model ◽  
Health Span ◽  
Healthy Older Adults ◽  
Age Related ◽  
Extended Lifespan ◽  
Disease Free

Abstract While insulin like growth factor-1 (IGF-1) is a well-established modulator of aging and longevity in model organisms, its role in humans is less well understood. Previous ambiguities in part have been attributed to cohort characteristics and unawareness of interactions between age and IGF-1. Centenarians have emerged as an ideal model of healthy aging because they delay the onset of age-related diseases and often remain disease free for the duration of their lifespan. In cohorts of centenarians and generally healthy older adults, we demonstrated that reduced IGF-1 is associated with extended lifespan and health-span. Additionally, we confirmed that IGF-1 interacts with age to modify risk in a manner consistent with antagonistic pleiotropy: younger individuals with high IGF-1 are protected from dementia, vascular disease, diabetes, cancer, and osteoporosis, while older individuals do not exhibit IGF-1-associated protection from disease. These findings offer evidence for IGF-1 modulating health-span and lifespan in humans.

scholarly journals Dietary restriction with and without caloric restriction for healthy aging

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 117 ◽  
Author(s):  
Changhan Lee ◽  
Valter Longo
Keyword(s):  
Adverse Effects ◽  
Caloric Restriction ◽  
Food Consumption ◽  
Dietary Restriction ◽  
Healthy Aging ◽  
Dietary Intervention ◽  
Model Organisms ◽  
Beneficial Effects ◽  
Dietary Restrictions ◽  
Safe Intervention

Caloric restriction is the most effective and reproducible dietary intervention known to regulate aging and increase the healthy lifespan in various model organisms, ranging from the unicellular yeast to worms, flies, rodents, and primates. However, caloric restriction, which in most cases entails a 20–40% reduction of food consumption relative to normal intake, is a severe intervention that results in both beneficial and detrimental effects. Specific types of chronic, intermittent, or periodic dietary restrictions without chronic caloric restriction have instead the potential to provide a significant healthspan increase while minimizing adverse effects. Improved periodic or targeted dietary restriction regimens that uncouple the challenge of food deprivation from the beneficial effects will allow a safe intervention feasible for a major portion of the population. Here we focus on healthspan interventions that are not chronic or do not require calorie restriction.

scholarly journals Time-Restricted Feeding and Caloric Restriction Impact on Spontaneous Neoplasms in Female Mice

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 128-128
Author(s):  
Annamaria Rudderow ◽  
Eleonora Duregon ◽  
Michel Bernier ◽  
Rafael de Cabo
Keyword(s):  
Caloric Restriction ◽  
Healthy Aging ◽  
Disease Onset ◽  
Caloric Intake ◽  
Malignant Neoplasm ◽  
Tumor Burden ◽  
Histiocytic Sarcoma ◽  
Model Organisms ◽  
Restricted Feeding ◽  
Female Mice

Abstract In older humans, multiple chronic diseases and increased life expectancy impose a disproportionate socioeconomic burden. Dietary interventions are valuable strategies for promoting healthy aging. Caloric restriction (CR) without malnutrition is a robust intervention able to delay disease onset and increase survival in model organisms. However, the impracticability of chronic CR outweighs the potential long-term benefits in humans. Time-restricted feeding (TRF), i.e. the limitation in the timing of food intake without necessarily reducing caloric intake, can protect against metabolic disorders through the synchronization of the circadian rhythm. This study compares whether limiting access to ad libitum (AL) food for a few hours per day mimics the beneficial effects of a CR diet. A large cohort of C57BL/6J female mice (n=250) was distributed into five feeding paradigms at midlife: AL, TRF for 8 hours, TRF for 4 hours, 20% CR and 20% CR fed twice a day (CRx2). Pathological analyses at death reveal a shift in fatal neoplasms toward an older age in TRF8 mice. AL mice had the highest prevalence of tumors (93%) and TRF4 had the lowest (77%). The highest tumor burden was observed in AL mice while CRx2 animals had the lowest number of neoplasms. Histiocytic sarcoma and lymphoma were the most represented malignancies, with CR mice exhibiting the highest rate of histiocytic sarcoma (75%) and the lowest rate of lymphoma (10%). These results indicate that time- and calorie-restricted feeding regimens can slow down malignant neoplasm progression and extend health span in female mice, even when started in adulthood.

scholarly journals Caloric Restriction Impedes Age-Related Decline of Mitochondrial Function and Neuronal Activity

2014 ◽  
Vol 34 (9) ◽  
pp. 1440-1443 ◽  
Author(s):  
Ai-Ling Lin ◽  
Daniel Coman ◽  
Lihong Jiang ◽  
Douglas L Rothman ◽  
Fahmeed Hyder
Keyword(s):  
Caloric Restriction ◽  
Neuronal Activity ◽  
Mitochondrial Function ◽  
Healthy Aging ◽  
Resonance Spectroscopy ◽  
Young Control ◽  
Brain Physiology ◽  
Age Related ◽  
Effects Of Aging

Caloric restriction (CR) prolongs lifespan and retards many detrimental effects of aging, but its effect on brain mitochondrial function and neuronal activity—especially in healthy aging—remains unexplored. Here we measured rates of neuronal glucose oxidation and glutamate–glutamine neurotransmitter cycling in young control, old control (i.e., healthy aging), and old CR rats using in vivo nuclear magnetic resonance spectroscopy. We found that, compared with the young control, neuronal energy production and neurotransmission rates were significantly reduced in healthy aging, but were preserved in old CR rats. The results suggest that CR mitigated the age-related deceleration of brain physiology.

scholarly journals Comparative study of protein aggregation propensity and mutation tolerance between naked mole-rat and mouse

2021 ◽  
Author(s):  
Savandara Besse ◽  
Raphaël Poujol ◽  
Julie G. Hussin
Keyword(s):  
Healthy Aging ◽  
Molecular Mechanisms ◽  
Therapeutic Interventions ◽  
Model Organisms ◽  
Protein Homeostasis ◽  
Aggregation Propensity ◽  
Age Related ◽  
Mole Rat ◽  
Significant Difference ◽  
Naked Mole Rat

The molecular mechanisms of aging and life expectancy have been studied in model organisms with short lifespans. However, long-lived species may provide insights into successful strategies of healthy aging, potentially opening the door for novel therapeutic interventions in age-related diseases. Notably, naked mole-rats, the longest-lived rodent, present attenuated aging phenotypes in comparison to mice. Their resistance toward oxidative stress has been proposed as one hallmark of their healthy aging, suggesting their ability to maintain cell homeostasis, and specifically their protein homeostasis. To identify the general principles behind their protein homeostasis robustness, we compared the aggregation propensity and mutation tolerance of naked mole-rat and mouse orthologous proteins. Our analysis showed no proteome-wide differential effects in aggregation propensity and mutation tolerance between these species, but several subsets of proteins with a significant difference in aggregation propensity. We found an enrichment of proteins with higher aggregation propensity in naked mole-rat involved the inflammasome complex, and in nucleic acid binding. On the other hand, proteins with lower aggregation propensity in naked mole-rat have a significantly higher mutation tolerance compared to the rest of the proteins. Among them, we identified proteins known to be associated with neurodegenerative and age-related diseases. These findings highlight the intriguing hypothesis about the capacity of the naked mole-rat proteome to delay aging through its proteomic intrinsic architecture.

scholarly journals Youthful and age-related matreotypes predict drugs promoting longevity

2021 ◽  
Author(s):  
Cyril Statzer ◽  
Elisabeth Jongsma ◽  
Sean X. Liu ◽  
Alexander Dakhovnik ◽  
Franziska Wandrey ◽  
...  
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Gene Expression Pattern ◽  
Surrogate Marker ◽  
Model Organisms ◽  
List Type ◽  
C Elegans ◽  
Drug Candidates ◽  
Matrix Gene ◽  
Age Related

AbstractThe identification and validation of drugs that promote health during aging (‘geroprotectors’) is key to the retardation or prevention of chronic age-related diseases. Here we found that most of the established pro-longevity compounds shown to extend lifespan in model organisms also alter extracellular matrix gene expression (i.e., matrisome) in human cell lines. To harness this novel observation, we used age-stratified human transcriptomes to define the age-related matreotype, which represents the matrisome gene expression pattern associated with age. Using a ‘youthful’ matreotype, we screened in silico for geroprotective drug candidates. To validate drug candidates, we developed a novel tool using prolonged collagen expression as a non-invasive and in-vivo surrogate marker for C. elegans longevity. With this reporter, we were able to eliminate false positive drug candidates and determine the appropriate dose for extending the lifespan of C. elegans. We improved drug uptake for one of our predicted compounds, genistein, and reconciled previous contradictory reports of its effects on longevity. We identified and validated new compounds, tretinoin, chondroitin sulfate, and hyaluronic acid, for their ability to restore age-related decline of collagen homeostasis and increase lifespan. Thus, our innovative drug screening approach - employing extracellular matrix homeostasis - facilitates the discovery of pharmacological interventions promoting healthy aging.HighlightsMany geroprotective drugs alter extracellular matrix gene expressionDefined young and old human matreotype signatures can identify novel potential geroprotective compoundsProlonged collagen homeostasis as a surrogate marker for longevity

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