bims-longev 2023-05-07 papers

bims-longev

Biomed News

on Longevity

Issue of 2023–05–07
thirteen papers selected by
Andreea Nitescu

Discovering Biological Mechanisms of Exceptional Human Health Span and Life Span.
Targeting the biology of aging with mTOR inhibitors.
The Tricarboxylic Acid Cycle as a Central Regulator of the Rate of Aging: Implications for Metabolic Interventions.
Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle.
Nutrition, immunity and aging: current scenario and future perspectives in neurodegenerative diseases.
Identification of fecal microbiome signatures associated with familial longevity and candidate metabolites for healthy aging.
The proteasome: A key modulator of nervous system function, brain aging, and neurodegenerative disease.
Mitigating age-related somatic mutation burden.
Mitophagy regulation in aging and neurodegenerative disease.
Editorial: Telomere length and species lifespan.
Mediterranean mechanisms of longevity.
Decoding Aging Hallmarks at the Single-Cell Level.
Hearing and Ageing.

Cold Spring Harb Perspect Med. 2023 May 03. pii: a041204. [Epub ahead of print]

Discovering Biological Mechanisms of Exceptional Human Health Span and Life Span.

Sofiya Milman, Nir Barzilai.

Humans age at different rates and families with exceptional longevity provide an opportunity to understand why some people age slower than others. Unique features exhibited by centenarians include a family history of extended life span, compression of morbidity with resultant extension of health span, and longevity-associated biomarker profiles. These biomarkers, including low-circulating insulin-like growth factor 1 (IGF-1) and elevated high-density lipoprotein (HDL) cholesterol levels, are associated with functional genotypes that are enriched in centenarians, suggesting that they may be causative for longevity. While not all genetic discoveries from centenarians have been validated, in part due to exceptional life span being a rare phenotype in the general population, the APOE2 and FOXO3a genotypes have been confirmed in a number of populations with exceptional longevity. However, life span is now recognized as a complex trait and genetic research methods to study longevity are rapidly extending beyond classical Mendelian genetics to polygenic inheritance methodologies. Moreover, newer approaches are suggesting that pathways that have been recognized for decades to control life span in animals may also regulate life span in humans. These discoveries led to strategic development of therapeutics that may delay aging and prolong health span.

DOI: https://doi.org/10.1101/cshperspect.a041204
Nat Aging. 2023 May 04.

Targeting the biology of aging with mTOR inhibitors.

Joan B Mannick, Dudley W Lamming.

Inhibition of the protein kinase mechanistic target of rapamycin (mTOR) with the Food and Drug Administration (FDA)-approved therapeutic rapamycin promotes health and longevity in diverse model organisms. More recently, specific inhibition of mTORC1 to treat aging-related conditions has become the goal of basic and translational scientists, clinicians and biotechnology companies. Here, we review the effects of rapamycin on the longevity and survival of both wild-type mice and mouse models of human diseases. We discuss recent clinical trials that have explored whether existing mTOR inhibitors can safely prevent, delay or treat multiple diseases of aging. Finally, we discuss how new molecules may provide routes to the safer and more selective inhibition of mTOR complex 1 (mTORC1) in the decade ahead. We conclude by discussing what work remains to be done and the questions that will need to be addressed to make mTOR inhibitors part of the standard of care for diseases of aging.

DOI: https://doi.org/10.1038/s43587-023-00416-y
Adv Biol (Weinh). 2023 May 02. e2300095

The Tricarboxylic Acid Cycle as a Central Regulator of the Rate of Aging: Implications for Metabolic Interventions.

Jonathan M Borkum.

  Certain metabolic interventions such as caloric restriction, fasting, exercise, and a ketogenic diet extend lifespan and/or health span. However, their benefits are limited and their connections to the underlying mechanisms of aging are not fully clear. Here, these connections are explored in terms of the tricarboxylic acid (TCA) cycle (Krebs cycle, citric acid cycle) to suggest reasons for the loss of effectiveness and ways of overcoming it. Specifically, the metabolic interventions deplete acetate and likely reduce the conversion of oxaloacetate to aspartate, thereby inhibiting the mammalian target of rapamycin (mTOR) and upregulating autophagy. Synthesis of glutathione may provide a high-capacity sink for amine groups, facilitating autophagy, and prevent buildup of alpha-ketoglutarate, supporting stem cell maintenance. Metabolic interventions also prevent the accumulation of succinate, thereby slowing DNA hypermethylation, facilitating the repair of DNA double-strand breaks, reducing inflammatory and hypoxic signaling, and lowering reliance on glycolysis. In part through these mechanisms, metabolic interventions may decelerate aging, extending lifespan. Conversely, with overnutrition or oxidative stress, these processes function in reverse, accelerating aging and impairing longevity. Progressive damage to aconitase, inhibition of succinate dehydrogenase, and downregulation of hypoxia-inducible factor-1α, and phosphoenolpyruvate carboxykinase (PEPCK) emerge as potentially modifiable reasons for the loss of effectiveness of metabolic interventions.

Keywords:  DNA methylation; DNA repair; aspartate; autophagy; hypoxia; succinate

DOI:  https://doi.org/10.1002/adbi.202300095
Aging Cell. 2023 May 02. e13859

Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle.

Sarah Voisin, Kirsten Seale, Macsue Jacques, Shanie Landen, Nicholas R Harvey, Larisa M Haupt, Lyn R Griffiths, Kevin J Ashton, Vernon G Coffey, Jamie-Lee M Thompson, Thomas M Doering, Malene E Lindholm, Colum Walsh, Gareth Davison, Rachelle Irwin, Catherine McBride, Ola Hansson, Olof Asplund, Aino E Heikkinen, Päivi Piirilä, Kirsi H Pietiläinen, Miina Ollikainen, Sara Blocquiaux, Martine Thomis, Coletta K Dawn, Adam P Sharples, Nir Eynon.

  Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late-life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown. Here, we performed a powerful meta-analysis of the methylome and transcriptome of an unprecedented number of human skeletal muscle samples (n = 3176). We show that: (1) individuals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, (2) exercise training leads to significant shifts of epigenetic and transcriptomic patterns toward a younger profile, and (3) muscle disuse "ages" the transcriptome. Higher fitness levels were associated with attenuated differential methylation and transcription during aging. Furthermore, both epigenetic and transcriptomic profiles shifted toward a younger state after exercise training interventions, while the transcriptome shifted toward an older state after forced muscle disuse. We demonstrate that exercise training targets many of the age-related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism, and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best combination of therapeutics and exercise regimes to optimize longevity.

Keywords:  DNA methylation; aging; cardiorespiratory fitness; exercise training; human skeletal muscle; mRNA expression; meta-analysis

DOI:  https://doi.org/10.1111/acel.13859
CNS Neurol Disord Drug Targets. 2023 May 02.

Nutrition, immunity and aging: current scenario and future perspectives in neurodegenerative diseases.

Camilla Barbero Mazzucca, Giuseppe Cappellano, Annalisa Chiocchetti.

  Aging is a gradual decline of physiological function and tissue homeostasis and, in many instances, is related to increased (neuro)-degeneration, together with inflammation, becoming one of the most important risks for developing neurodegenerative diseases. Certain individual nutrients or foods in combination may counteract aging and associated neurodegenerative diseases by promoting a balance between the pro- and anti-inflammatory responses. Thus, nutrition could represent a powerful modulator of this fine balance, other than a modifiable risk factor to contrast inflammaging. This narrative review explores from a broad perspective the impact of nutrition on the hallmarks of aging and inflammation in Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis Syndrome (ALS), starting from nutrients up to single foods and complex dietary patterns.

Keywords:  Alzheimer; Amyotrophic lateral sclerosis; Parkinson; aging; inflammation; nutrition

DOI:  https://doi.org/10.2174/1871527322666230502123255
Aging Cell. 2023 May 02. e13848

Identification of fecal microbiome signatures associated with familial longevity and candidate metabolites for healthy aging.

Junli Gong, Sanxin Liu, Shisi Wang, Hengfang Ruan, Qianqian Mou, Ping Fan, Tao Chen, Wei Cai, Yongjun Lu, Zhengqi Lu.

  Gut microbiota associated with longevity plays an important role in the adaptation to damaging stimuli accumulated during the aging process. The mechanism by which the longevity-associated microbiota protects the senescent host remains unclear, while the metabolites of the gut bacteria are of particular interest. Here, an integrated analysis of untargeted metabolomics and 16S rRNA gene sequencing was used to characterize the metabolite and microbiota profiles of long-lived individuals (aged ≥90 years) in comparison to old-elderly (aged 75-89 years), young-elderly (aged 60-74 years), and young to middle-aged (aged ≤59 years) individuals. This novel study constructed both metabolite and microbiota trajectories across aging in populations from Jiaoling county (the seventh longevity town of the world) in China. We found that the long-lived group exhibited remarkably differential metabolomic signatures, highlighting the existence of metabolic heterogeneity with aging. Importantly, we also discovered that long-lived individuals from the familial longevity cohort harbored a microbiome distinguished from that of the general population. Specifically, we identified that the levels of a candidate metabolite, pinane thromboxane A2 (PTA2), which is positively associated with aging, were consistently higher in individuals with familial longevity and their younger descendants than in those of the general population. Furtherly, functional analysis revealed that PTA2 potentiated the efficiency of microglial phagocytosis of β-amyloid 40 and enhanced an anti-inflammatory phenotype, indicating a protective role of PTA2 toward host health. Collectively, our results improve the understanding of the role of the gut microbiome in longevity and may facilitate the development of strategies for healthy aging.

Keywords:  familial longevity; fecal microbiome; healthy aging; pinane thromboxane A2

DOI:  https://doi.org/10.1111/acel.13848
Front Cell Dev Biol. 2023 ;11 1124907

The proteasome: A key modulator of nervous system function, brain aging, and neurodegenerative disease.

Kanisa Davidson, Andrew M Pickering.

  The proteasome is a large multi-subunit protease responsible for the degradation and removal of oxidized, misfolded, and polyubiquitinated proteins. The proteasome plays critical roles in nervous system processes. This includes maintenance of cellular homeostasis in neurons. It also includes roles in long-term potentiation via modulation of CREB signaling. The proteasome also possesses roles in promoting dendritic spine growth driven by proteasome localization to the dendritic spines in an NMDA/CaMKIIα dependent manner. Proteasome inhibition experiments in varied organisms has been shown to impact memory, consolidation, recollection and extinction. The proteasome has been further shown to impact circadian rhythm through modulation of a range of 'clock' genes, and glial function. Proteasome function is impaired as a consequence both of aging and neurodegenerative diseases. Many studies have demonstrated an impairment in 26S proteasome function in the brain and other tissues as a consequence of age, driven by a disassembly of 26S proteasome in favor of 20S proteasome. Some studies also show proteasome augmentation to correct age-related deficits. In amyotrophic lateral sclerosis Alzheimer's, Parkinson's and Huntington's disease proteasome function is impaired through distinct mechanisms with impacts on disease susceptibility and progression. Age and neurodegenerative-related deficits in the function of the constitutive proteasome are often also accompanied by an increase in an alternative form of proteasome called the immunoproteasome. This article discusses the critical role of the proteasome in the nervous system. We then describe how proteasome dysfunction contributes to brain aging and neurodegenerative disease.

Keywords:  Alzheimer’s disease; Parkinson's disease; brain aging; huntington’s disease; immunoproteasome; proteasome; synaptic plasticity; ubiquitin proteasomal system

DOI:  https://doi.org/10.3389/fcell.2023.1124907
Trends Mol Med. 2023 Apr 28. pii: S1471-4914(23)00072-2. [Epub ahead of print]

Mitigating age-related somatic mutation burden.

Jan Vijg, Björn Schumacher, Abdulkadir Abakir, Michael Antonov, Chris Bradley, Alex Cagan, George Church, Vadim N Gladyshev, Vera Gorbunova, Alexander Y Maslov, Wolf Reik, Samim Sharifi, Yousin Suh, Kenneth Walsh.

  Genomes are inherently unstable and require constant DNA repair to maintain their genetic information. However, selective pressure has optimized repair mechanisms in somatic cells only to allow transmitting genetic information to the next generation, not to maximize sequence integrity long beyond the reproductive age. Recent studies have confirmed that somatic mutations, due to errors during genome repair and replication, accumulate in tissues and organs of humans and model organisms. Here, we describe recent advances in the quantitative analysis of somatic mutations in vivo. We also review evidence for or against a possible causal role of somatic mutations in aging. Finally, we discuss options to prevent, delay or eliminate de novo, random somatic mutations as a cause of aging.

Keywords:  aging; cancer; chromatin organization; clonal hematopoiesis; germline versus somatic genome; somatic mutations

DOI:  https://doi.org/10.1016/j.molmed.2023.04.002
Biophys Rev. 2023 Apr;15(2): 239-255

Mitophagy regulation in aging and neurodegenerative disease.

Trupti A Banarase, Shivkumar S Sammeta, Nitu L Wankhede, Shubhada V Mangrulkar, Sandip R Rahangdale, Manish M Aglawe, Brijesh G Taksande, Aman B Upaganlawar, Milind J Umekar, Mayur B Kale.

  Mitochondria are the primary cellular energy generators, supplying the majority of adenosine triphosphate through oxidative phosphorylation, which is necessary for neuron function and survival. Mitophagy is the metabolic process of eliminating dysfunctional or redundant mitochondria. It is a type of autophagy and it is crucial for maintaining mitochondrial and neuronal health. Impaired mitophagy leads to an accumulation of damaged mitochondria and proteins leading to the dysregulation of mitochondrial quality control processes. Recent research shows the vital role of mitophagy in neurons and the pathogenesis of major neurodegenerative diseases. Mitophagy also plays a major role in the process of aging. This review describes the alterations that are being caused in the mitophagy process at the molecular level in aging and in neurodegenerative diseases, particularly Alzheimer's, Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis, also looks at how mitophagy can be exploited as a therapeutic target for these diseases.

Keywords:  Aging; Alzheimer’s disease; Amyotrophic lateral sclerosis; Mitochondria; Mitophagy; Neurodegenerative diseases; Parkinson’s disease

DOI:  https://doi.org/10.1007/s12551-023-01057-6
Front Genet. 2023 ;14 1199667

Editorial: Telomere length and species lifespan.

Kurt Whittemore, Michael Fossel.



Keywords:  body mass; cellular senescence; species lifespan; telomere shortening rate; telomeres

DOI:  https://doi.org/10.3389/fgene.2023.1199667
Nat Cell Biol. 2023 May 01.

Mediterranean mechanisms of longevity.

Alexander Richard Mendenhall.

DOI: https://doi.org/10.1038/s41556-023-01115-x
Annu Rev Biomed Data Sci. 2023 Apr 26.

Decoding Aging Hallmarks at the Single-Cell Level.

Shuai Ma, Xu Chi, Yusheng Cai, Zhejun Ji, Si Wang, Jie Ren, Guang-Hui Liu.

Organismal aging exhibits wide-ranging hallmarks in divergent cell types across tissues, organs, and systems. The advancement of single-cell technologies and generation of rich datasets have afforded the scientific community the opportunity to decode these hallmarks of aging at an unprecedented scope and resolution. In this review, we describe the technological advancements and bioinformatic methodologies enabling data interpretation at the cellular level. Then, we outline the application of such technologies for decoding aging hallmarks and potential intervention targets and summarize common themes and context-specific molecular features in representative organ systems across the body. Finally, we provide a brief summary of available databases relevant for aging research and present an outlook on the opportunities in this emerging field. Expected final online publication date for the Annual Review of Biomedical Data Science, Volume 6 is August 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-biodatasci-020722-120642
Subcell Biochem. 2023 ;103 279-290

Hearing and Ageing.

Mariapia Guerrieri, Roberta Di Mauro, Stefano Di Girolamo, Arianna Di Stadio.

  Age-related hearing loss (ARHL), or presbycusis, occurs in most mammals, humans included, with a different age of onset and magnitude of loss. It is associated with two major symptoms: loss of sensitivity to sound, especially for high pitches, and a reduced ability to understand speech in background noise. This phenomenon involves both the peripheral structures of the inner ear and the central acoustic pathways. Several mechanisms have been identified as pro-ageing in the human cochlea. The main one is the oxidative stress. The inner ear physiological degeneration can be affected by both intrinsic conditions, such as genetic predisposition, and extrinsic ones, such as noise exposure. The magnitude of neuronal loss precedes and exceeds that of inner hair cell loss, which is also less important than the loss of outer hair cells. Patients with HL often develop atrophy of the temporal lobe (auditory cortex) and brain gliosis can contribute to the development of a central hearing loss. The presence of white matter hyperintensities (WMHs) on the MRI, which is radiologic representation of brain gliosis, can justify a central HL due to demyelination in the superior auditory pathways. Recently, the presence of WMHs has been correlated with the inability to correctly understand words in elderly with normal auditory thresholds.

Keywords:  Ageing; Hair cells; Hearing loss; Inner ear; Mitochondria; ROS; Spiral ganglions

DOI:  https://doi.org/10.1007/978-3-031-26576-1_12