bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2023–05–07
nine papers selected by
Ayesh Seneviratne, Western University
  1. Mitigating age-related somatic mutation burden.
  2. Targeting the biology of aging with mTOR inhibitors.
  3. The Tricarboxylic Acid Cycle as a Central Regulator of the Rate of Aging: Implications for Metabolic Interventions.
  4. Telomere Length and Clonal Hematopoiesis.
  5. Lipid droplets and peroxisomes are co-regulated to drive lifespan extension in response to mono-unsaturated fatty acids.
  6. Astrocytes in Ageing.
  7. Familial Clonal Hematopoiesis in a Long Telomere Syndrome.
  8. Editorial: The neuroscience of advancing age.
  9. The effect of metformin on influenza vaccine responses in nondiabetic older adults: a pilot trial.
  1. 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
  2. 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
  3. 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
  4. N Engl J Med. 2023 May 04.
    Telomere Length and Clonal Hematopoiesis.
    George Vassiliou.
      
    DOI:  https://doi.org/10.1056/NEJMe2303022
  5. Nat Cell Biol. 2023 May 01.
    Lipid droplets and peroxisomes are co-regulated to drive lifespan extension in response to mono-unsaturated fatty acids.
    Katharina Papsdorf, Jason W Miklas, Amir Hosseini, Matias Cabruja, Christopher S Morrow, Marzia Savini, Yong Yu, Carlos G Silva-García, Nicole R Haseley, Luke Meraz Murphy, Pallas Yao, Elisa de Launoit, Scott J Dixon, Michael P Snyder, Meng C Wang, William B Mair, Anne Brunet.
      Dietary mono-unsaturated fatty acids (MUFAs) are linked to longevity in several species. But the mechanisms by which MUFAs extend lifespan remain unclear. Here we show that an organelle network involving lipid droplets and peroxisomes is critical for MUFA-induced longevity in Caenorhabditis elegans. MUFAs upregulate the number of lipid droplets in fat storage tissues. Increased lipid droplet number is necessary for MUFA-induced longevity and predicts remaining lifespan. Lipidomics datasets reveal that MUFAs also modify the ratio of membrane lipids and ether lipids-a signature associated with decreased lipid oxidation. In agreement with this, MUFAs decrease lipid oxidation in middle-aged individuals. Intriguingly, MUFAs upregulate not only lipid droplet number but also peroxisome number. A targeted screen identifies genes involved in the co-regulation of lipid droplets and peroxisomes, and reveals that induction of both organelles is optimal for longevity. Our study uncovers an organelle network involved in lipid homeostasis and lifespan regulation, opening new avenues for interventions to delay aging.
    DOI:  https://doi.org/10.1038/s41556-023-01136-6
  6. Subcell Biochem. 2023 ;103 253-277
    Astrocytes in Ageing.
    Alexei Verkhratsky, Alexey Semyanov.
      Ageing is associated with a morphological and functional decline of astrocytes with a prevalence of morphological atrophy and loss of function. In particular, ageing is manifested by the shrinkage of astrocytic processes: branches and leaflets, which decreases synaptic coverage. Astrocytic dystrophy affects multiple functions astrocytes play in the brain active milieu. In particular, and in combination with an age-dependent decline in the expression of glutamate transporters, astrocytic atrophy translates into deficient glutamate clearance and K+ buffering. Decreased astrocyte presence may contribute to age-dependent remodelling of brain extracellular space, hence affecting extrasynaptic signalling. Old astrocytes lose endfeet polarisation of AQP4 water channels, thus limiting the operation of the glymphatic system. In ageing, astrocytes down-regulate their antioxidant capacity leading to decreased neuroprotection. All these changes may contribute to an age-dependent cognitive decline.
    Keywords:  Ageing; Astrocyte; Astroglial function; Astroglial perisynaptic cradle; Neuroplasticity; Reactive astrogliosis; Synaptic transmission
    DOI:  https://doi.org/10.1007/978-3-031-26576-1_11
  7. N Engl J Med. 2023 May 04.
    Familial Clonal Hematopoiesis in a Long Telomere Syndrome.
    Emily A DeBoy, Michael G Tassia, Kristen E Schratz, Stephanie M Yan, Zoe L Cosner, Emily J McNally, Dustin L Gable, Zhimin Xiang, David B Lombard, Emmanuel S Antonarakis, Christopher D Gocke, Rajiv C McCoy, Mary Armanios.
       BACKGROUND: Telomere shortening is a well-characterized cellular aging mechanism, and short telomere syndromes cause age-related disease. However, whether long telomere length is advantageous is poorly understood.
    METHODS: We examined the clinical and molecular features of aging and cancer in persons carrying heterozygous loss-of-function mutations in the telomere-related gene POT1 and noncarrier relatives.
    RESULTS: A total of 17 POT1 mutation carriers and 21 noncarrier relatives were initially included in the study, and a validation cohort of 6 additional mutation carriers was subsequently recruited. A majority of the POT1 mutation carriers with telomere length evaluated (9 of 13) had long telomeres (>99th percentile). POT1 mutation carriers had a range of benign and malignant neoplasms involving epithelial, mesenchymal, and neuronal tissues in addition to B- and T-cell lymphoma and myeloid cancers. Five of 18 POT1 mutation carriers (28%) had T-cell clonality, and 8 of 12 (67%) had clonal hematopoiesis of indeterminate potential. A predisposition to clonal hematopoiesis had an autosomal dominant pattern of inheritance, as well as penetrance that increased with age; somatic DNMT3A and JAK2 hotspot mutations were common. These and other somatic driver mutations probably arose in the first decades of life, and their lineages secondarily accumulated a higher mutation burden characterized by a clocklike signature. Successive generations showed genetic anticipation (i.e., an increasingly early onset of disease). In contrast to noncarrier relatives, who had the typical telomere shortening with age, POT1 mutation carriers maintained telomere length over the course of 2 years.
    CONCLUSIONS: POT1 mutations associated with long telomere length conferred a predisposition to a familial clonal hematopoiesis syndrome that was associated with a range of benign and malignant solid neoplasms. The risk of these phenotypes was mediated by extended cellular longevity and by the capacity to maintain telomeres over time. (Funded by the National Institutes of Health and others.).
    DOI:  https://doi.org/10.1056/NEJMoa2300503
  8. Front Aging Neurosci. 2023 ;15 1195785
    Editorial: The neuroscience of advancing age.
    Ann-Maree Vallence, Rachael D Seidler, Mitchell Ryan Goldsworthy, John G Semmler, George M Opie.
      
    Keywords:  NIBS; healthy aging; neuroimaging; neuromodulation; pathological aging
    DOI:  https://doi.org/10.3389/fnagi.2023.1195785
  9. Immun Ageing. 2023 May 02. 20(1): 18
    The effect of metformin on influenza vaccine responses in nondiabetic older adults: a pilot trial.
    Dominique E Martin, Andreia N Cadar, Hunter Panier, Blake L Torrance, George A Kuchel, Jenna M Bartley.
       BACKGROUND: Aging is associated with progressive declines in immune responses leading to increased risk of severe infection and diminished vaccination responses. Influenza (flu) is a leading killer of older adults despite availability of seasonal vaccines. Geroscience-guided interventions targeting biological aging could offer transformational approaches to reverse broad declines in immune responses with aging. Here, we evaluated effects of metformin, an FDA approved diabetes drug and candidate anti-aging drug, on flu vaccination responses and markers of immunological resilience in a pilot and feasibility double-blinded placebo-controlled study.
    RESULTS: Healthy older adults (non-diabetic/non-prediabetic, age: 74.4 ± 1.7 years) were randomized to metformin (n = 8, 1500 mg extended release/daily) or placebo (n = 7) treatment for 20 weeks and were vaccinated with high-dose flu vaccine after 10 weeks of treatment. Peripheral blood mononuclear cells (PBMCs), serum, and plasma were collected prior to treatment, immediately prior to vaccination, and 1, 5, and 10 weeks post vaccination. Increased serum antibody titers were observed post vaccination with no significant differences between groups. Metformin treatment led to trending increases in circulating T follicular helper cells post-vaccination. Furthermore, 20 weeks of metformin treatment reduced expression of exhaustion marker CD57 in circulating CD4 T cells.
    CONCLUSIONS: Pre-vaccination metformin treatment improved some components of flu vaccine responses and reduced some markers of T cell exhaustion without serious adverse events in nondiabetic older adults. Thus, our findings highlight the potential utility of metformin to improve flu vaccine responses and reduce age-related immune exhaustion in older adults, providing improved immunological resilience in nondiabetic older adults.
    Keywords:  Aging; Geroscience-guided clinical trial; Immune exhaustion; Metformin; Vaccination
    DOI:  https://doi.org/10.1186/s12979-023-00343-x
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