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Molecular and Biological Mechanisms of Longevity

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 28851

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Prof. Dr. Irmgard Tegeder

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Pharmazentrum Frankfurt, Dept. of Clinical Pharmacology, Goethe-University of Frankfurt, Theodor Stern Kai 7, Bd. 74, 4th Fl, 60590 Frankfurt am Main, Germany
Interests: nerve injury and neuropathic pain; pain and aging; central adaptations to chronic pain; multiple sclerosis; neuroinflammation; neuro-immunologic communication; redox signaling; nitric oxide; endocannabinoids and other lipid signaling molecules; progranulin; autophagy
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Dear Colleagues,

Longevity, in the sense of maintaining a long and healthy life, is influenced by genes and environmental factors. Particularly, modulation of the latter has gained recent interest for the prevention of disease and aging. The molecular and cell biological mechanisms that help to maintain a long and healthy life are not simply the opposite of aging, but characterized by a positive gain of resource-sparing functions such as change of enzyme activity, enhancement of cellular waste clearance, or adaptations to mild challenges, which increase the resilience towards major stressors. The maintenance of the cellular homeostasis of nutrients, metabolites, redox states, proteins, RNA molecules, etc. is a major challenge. It is particularly intriguing to unravel how for example intermittent undulations caused by physical and mental exercise, intermittent fasting, social events, or resetting of the internal clocks help to extend the individual’s life.

In the present Special Issue, we invite contributions addressing molecular and biological mechanisms of longevity, including all aspects from genetic, epigenetic, metabolic, endocrine, immune, or redox-mediated mechanisms to environmental factors such as nutrition, sleep, social life, or exercise. Original research papers and reviews are equally welcome, and may involve in vitro and in vivo studies in different cells and organisms. The Special Issue will emphasize common and specific mechanisms adopted by various organisms to maintain a long and healthy life and highlight translational aspects ranging from molecules to human life at old age.

Prof. Dr. Irmgard Tegeder
Guest Editor

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Keywords

Longevity
Lifespan
Health
Senescence
Homeostasis
Proteostasis
Nutrition
Redox balance
Metabolic balance

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Published Papers (7 papers)

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Research

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14 pages, 3070 KiB

Open AccessArticle

Isocitrate Dehydrogenase Alpha-1 Modulates Lifespan and Oxidative Stress Tolerance in Caenorhabditis elegans

by Zhi-Han Lin, Shun-Ya Chang, Wen-Chi Shen, Yen-Hung Lin, Chiu-Lun Shen, Sin-Bo Liao, Yu-Chun Liu, Chang-Shi Chen, Tsui-Ting Ching and Horng-Dar Wang

Int. J. Mol. Sci. 2023, 24(1), 612; https://doi.org/10.3390/ijms24010612 - 29 Dec 2022

Viewed by 2296

Abstract

Altered metabolism is a hallmark of aging. The tricarboxylic acid cycle (TCA cycle) is an essential metabolic pathway and plays an important role in lifespan regulation. Supplementation of α-ketoglutarate, a metabolite converted by isocitrate dehydrogenase alpha-1 (idha-1) in the TCA cycle, increases lifespan in C. elegans. However, whether idha-1 can regulate lifespan in C. elegans remains unknown. Here, we reported that the expression of idha-1 modulates lifespan and oxidative stress tolerance in C. elegans. Transgenic overexpression of idha-1 extends lifespan, increases the levels of NADPH/NADP⁺ ratio, and elevates the tolerance to oxidative stress. Conversely, RNAi knockdown of idha-1 exhibits the opposite effects. In addition, the longevity of eat-2 (ad1116) mutant via dietary restriction (DR) was reduced by idha-1 knockdown, indicating that idha-1 may play a role in DR-mediated longevity. Furthermore, idha-1 mediated lifespan may depend on the target of rapamycin (TOR) signaling. Moreover, the phosphorylation levels of S6 kinase (p-S6K) inversely correlate with idha-1 expression, supporting that the idha-1-mediated lifespan regulation may involve the TOR signaling pathway. Together, our data provide new insights into the understanding of idha-1 new function in lifespan regulation probably via DR and TOR signaling and in oxidative stress tolerance in C. elegans. Full article

(This article belongs to the Special Issue Molecular and Biological Mechanisms of Longevity)

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16 pages, 2645 KiB

Open AccessArticle

Telomere Length Is Correlated with Resting Metabolic Rate and Aerobic Capacity in Women: A Cross-Sectional Study

by Rujira Nonsa-ard, Ploypailin Aneknan, Terdthai Tong-un, Sittisak Honsawek, Chanvit Leelayuwat and Naruemon Leelayuwat

Int. J. Mol. Sci. 2022, 23(21), 13336; https://doi.org/10.3390/ijms232113336 - 1 Nov 2022

Cited by 3 | Viewed by 2011

Abstract

This study investigated the associations between relative telomere length (RTL) and resting metabolic rate (RMR), resting fat oxidation (RFO), and aerobic capacity and whether oxidative stress and inflammation are the underlying mechanisms in sedentary women. We also aimed to determine whether the correlations depend on age and obesity. Sixty-eight normal weight and 66 obese women participated in this study. After adjustment for age, energy expenditure, energy intake, and education level, the RTL of all participants was negatively correlated with absolute RMR (RMR_AB) and serum high-sensitivity C-reactive protein (hsCRP) concentration, and positively correlated with maximum oxygen consumption (

\dot{V}

O_2max) (all p < 0.05). After additional adjustment for adiposity indices and fat-free mass (FFM), RTL was positively correlated with plasma vitamin C concentration (p < 0.05). Furthermore, after adjustment for fasting blood glucose concentration, RTL was negatively correlated with age and positively correlated with

\dot{V}

O_2max (mL/kg FFM/min). We found that normal weight women had longer RTL than obese women (p < 0.001). We suggest that RTL is negatively correlated with RMR_AB and positively correlated with aerobic capacity, possibly via antioxidant and anti-inflammatory mechanisms. Furthermore, age and obesity influenced the associations. We provide useful information for the management of promotion strategies for health-related physical fitness in women. Full article

(This article belongs to the Special Issue Molecular and Biological Mechanisms of Longevity)

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15 pages, 1740 KiB

Open AccessArticle

Long-Lived Individuals Show a Lower Burden of Variants Predisposing to Age-Related Diseases and a Higher Polygenic Longevity Score

by Guillermo G. Torres, Janina Dose, Tim P. Hasenbein, Marianne Nygaard, Ben Krause-Kyora, Jonas Mengel-From, Kaare Christensen, Karen Andersen-Ranberg, Daniel Kolbe, Wolfgang Lieb, Matthias Laudes, Siegfried Görg, Stefan Schreiber, Andre Franke, Amke Caliebe, Gregor Kuhlenbäumer and Almut Nebel

Int. J. Mol. Sci. 2022, 23(18), 10949; https://doi.org/10.3390/ijms231810949 - 19 Sep 2022

Cited by 10 | Viewed by 3173

Abstract

Longevity is a complex phenotype influenced by both environmental and genetic factors. The genetic contribution is estimated at about 25%. Despite extensive research efforts, only a few longevity genes have been validated across populations. Long-lived individuals (LLI) reach extreme ages with a relative low prevalence of chronic disability and major age-related diseases (ARDs). We tested whether the protection from ARDs in LLI can partly be attributed to genetic factors by calculating polygenic risk scores (PRSs) for seven common late-life diseases (Alzheimer’s disease (AD), atrial fibrillation (AF), coronary artery disease (CAD), colorectal cancer (CRC), ischemic stroke (ISS), Parkinson’s disease (PD) and type 2 diabetes (T2D)). The examined sample comprised 1351 German LLI (≥94 years, including 643 centenarians) and 4680 German younger controls. For all ARD-PRSs tested, the LLI had significantly lower scores than the younger control individuals (areas under the curve (AUCs): ISS = 0.59, p = 2.84 × 10⁻³⁵; AD = 0.59, p = 3.16 × 10⁻²⁵; AF = 0.57, p = 1.07 × 10⁻¹⁶; CAD = 0.56, p = 1.88 × 10⁻¹²; CRC = 0.52, p = 5.85 × 10⁻³; PD = 0.52, p = 1.91 × 10⁻³; T2D = 0.51, p = 2.61 × 10⁻³). We combined the individual ARD-PRSs into a meta-PRS (AUC = 0.64, p = 6.45 × 10⁻¹⁵). We also generated two genome-wide polygenic scores for longevity, one with and one without the TOMM40/APOE/APOC1 gene region (AUC (incl. TOMM40/APOE/APOC1) = 0.56, p = 1.45 × 10⁻⁵, seven variants; AUC (excl. TOMM40/APOE/APOC1) = 0.55, p = 9.85 × 10⁻³, 10,361 variants). Furthermore, the inclusion of nine markers from the excluded region (not in LD with each other) plus the APOE haplotype into the model raised the AUC from 0.55 to 0.61. Thus, our results highlight the importance of TOMM40/APOE/APOC1 as a longevity hub. Full article

(This article belongs to the Special Issue Molecular and Biological Mechanisms of Longevity)

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17 pages, 2446 KiB

Open AccessArticle

Lifespan Extension of Podospora anserina Mic60-Subcomplex Mutants Depends on Cardiolipin Remodeling

by Lisa-Marie Marschall, Verena Warnsmann, Anja C. Meeßen, Timo Löser and Heinz D. Osiewacz

Int. J. Mol. Sci. 2022, 23(9), 4741; https://doi.org/10.3390/ijms23094741 - 25 Apr 2022

Cited by 5 | Viewed by 2188

Abstract

Function of mitochondria largely depends on a characteristic ultrastructure with typical invaginations, namely the cristae of the inner mitochondrial membrane. The mitochondrial signature phospholipid cardiolipin (CL), the F₁F_o-ATP-synthase, and the ‘mitochondrial contact site and cristae organizing system’ (MICOS) complex are involved in this process. Previous studies with Podospora anserina demonstrated that manipulation of MICOS leads to altered cristae structure and prolongs lifespan. While longevity of Mic10-subcomplex mutants is induced by mitohormesis, the underlying mechanism in the Mic60-subcomplex deletion mutants was unclear. Since several studies indicated a connection between MICOS and phospholipid composition, we now analyzed the impact of MICOS on mitochondrial phospholipid metabolism. Data from lipidomic analysis identified alterations in phospholipid profile and acyl composition of CL in Mic60-subcomplex mutants. These changes appear to have beneficial effects on membrane properties and promote longevity. Impairments of CL remodeling in a PaMIC60 ablated mutant lead to a complete abrogation of longevity. This effect is reversed by supplementation of the growth medium with linoleic acid, a fatty acid which allows the formation of tetra-octadecanoyl CL. In the PaMic60 deletion mutant, this CL species appears to lead to longevity. Overall, our data demonstrate a tight connection between MICOS, the regulation of mitochondrial phospholipid homeostasis, and aging of P. anserina. Full article

(This article belongs to the Special Issue Molecular and Biological Mechanisms of Longevity)

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Review

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11 pages, 576 KiB

Open AccessReview

Progress in Discovering Transcriptional Noise in Aging

by Josh Bartz, Hannim Jung, Karen Wasiluk, Lei Zhang and Xiao Dong

Int. J. Mol. Sci. 2023, 24(4), 3701; https://doi.org/10.3390/ijms24043701 - 12 Feb 2023

Cited by 5 | Viewed by 3460

Abstract

Increasing stochasticity is a key feature in the aging process. At the molecular level, in addition to genome instability, a well-recognized hallmark of aging, cell-to-cell variation in gene expression was first identified in mouse hearts. With the technological breakthrough in single-cell RNA sequencing, most studies performed in recent years have demonstrated a positive correlation between cell-to-cell variation and age in human pancreatic cells, as well as mouse lymphocytes, lung cells, and muscle stem cells during senescence in vitro. This phenomenon is known as the “transcriptional noise” of aging. In addition to the increasing evidence in experimental observations, progress also has been made to better define transcriptional noise. Traditionally, transcriptional noise is measured using simple statistical measurements, such as the coefficient of variation, Fano factor, and correlation coefficient. Recently, multiple novel methods have been proposed, e.g., global coordination level analysis, to define transcriptional noise based on network analysis of gene-to-gene coordination. However, remaining challenges include a limited number of wet-lab observations, technical noise in single-cell RNA sequencing, and the lack of a standard and/or optimal data analytical measurement of transcriptional noise. Here, we review the recent technological progress, current knowledge, and challenges to better understand transcriptional noise in aging. Full article

(This article belongs to the Special Issue Molecular and Biological Mechanisms of Longevity)

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33 pages, 3721 KiB

Open AccessReview

Why Is Longevity Still a Scientific Mystery? Sirtuins—Past, Present and Future

by Patrycja Ziętara, Marta Dziewięcka and Maria Augustyniak

Int. J. Mol. Sci. 2023, 24(1), 728; https://doi.org/10.3390/ijms24010728 - 31 Dec 2022

Cited by 21 | Viewed by 8602

Abstract

The sirtuin system consists of seven highly conserved regulatory enzymes responsible for metabolism, antioxidant protection, and cell cycle regulation. The great interest in sirtuins is associated with the potential impact on life extension. This article summarizes the latest research on the activity of sirtuins and their role in the aging process. The effects of compounds that modulate the activity of sirtuins were discussed, and in numerous studies, their effectiveness was demonstrated. Attention was paid to the role of a caloric restriction and the risks associated with the influence of careless sirtuin modulation on the organism. It has been shown that low modulators’ bioavailability/retention time is a crucial problem for optimal regulation of the studied pathways. Therefore, a detailed understanding of the modulator structure and potential reactivity with sirtuins in silico studies should precede in vitro and in vivo experiments. The latest achievements in nanobiotechnology make it possible to create promising molecules, but many of them remain in the sphere of plans and concepts. It seems that solving the mystery of longevity will have to wait for new scientific discoveries. Full article

(This article belongs to the Special Issue Molecular and Biological Mechanisms of Longevity)

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16 pages, 508 KiB

Open AccessReview

Nutraceutical and Dietary Strategies for Up-Regulating Macroautophagy

by Mark F. McCarty

Int. J. Mol. Sci. 2022, 23(4), 2054; https://doi.org/10.3390/ijms23042054 - 12 Feb 2022

Cited by 12 | Viewed by 5381

Abstract

Macroautophagy is a “cell cleansing” process that rids cells of protein aggregates and damaged organelles that may contribute to disease pathogenesis and the dysfunctions associated with aging. Measures which boost longevity and health span in rodents typically up-regulate macroautophagy, and it has often been suggested that safe strategies which can promote this process in humans may contribute to healthful aging. The kinase ULK1 serves as a trigger for autophagy initiation, and the transcription factors TFEB, FOXO1, ATF4 and CHOP promote expression of a number of proteins which mediate macroautophagy. Nutraceutical or dietary measures which stimulate AMPK, SIRT1, eIF5A, and that diminish the activities of AKT and mTORC1, can be expected to boost the activities of these pro-autophagic factors. The activity of AMPK can be stimulated with the phytochemical berberine. SIRT1 activation may be achieved with a range of agents, including ferulic acid, melatonin, urolithin A, N1-methylnicotinamide, nicotinamide riboside, and glucosamine; correction of ubiquinone deficiency may also be useful in this regard, as may dietary strategies such as time-restricted feeding or intermittent fasting. In the context of an age-related decrease in cellular polyamine levels, provision of exogenous spermidine can boost the hypusination reaction required for the appropriate post-translational modification of eIF5A. Low-protein plant-based diets could be expected to increase ATF4 and CHOP expression, while diminishing IGF-I-mediated activation of AKT and mTORC1. Hence, practical strategies for protecting health by up-regulating macroautophagy may be feasible. Full article

(This article belongs to the Special Issue Molecular and Biological Mechanisms of Longevity)

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