bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–08–14
nine papers selected by
Ayesh Seneviratne, Western University



  1. Cell Mol Life Sci. 2022 Aug 08. 79(9): 473
      Hematopoietic stem cells (HSCs) undergo progressive functional decline over time due to both internal and external stressors, leading to aging of the hematopoietic system. A comprehensive understanding of the molecular mechanisms underlying HSC aging will be valuable in developing novel therapies for HSC rejuvenation and to prevent the onset of several age-associated diseases and hematological malignancies. This review considers the general causes of HSC aging that range from cell-intrinsic factors to cell-extrinsic factors. In particular, epigenetics and inflammation have been implicated in the linkage of HSC aging, clonality, and oncogenesis. The challenges in clarifying mechanisms of HSC aging have accelerated the development of therapeutic interventions to rejuvenate HSCs, the major goal of aging research; these details are also discussed in this review.
    Keywords:  Aging; Clonal hematopoiesis; Hematological malignancy; Hematopoietic stem cell; Rejuvenation
    DOI:  https://doi.org/10.1007/s00018-022-04356-5
  2. Aging (Albany NY). 2022 Aug 06. undefined(undefined):
      
    Keywords:  NAD +; aging; exercise; frailty; healthspan
    DOI:  https://doi.org/10.18632/aging.204220
  3. Age Ageing. 2022 Aug 02. pii: afac179. [Epub ahead of print]51(8):
      As people age they are at increased risk of cardiovascular disease, the leading cause of mortality and morbidity worldwide. Understanding cardiovascular ageing is essential to preserving healthy ageing and preventing serious health outcomes. This collection of papers published in Age and Ageing since 2011 cover key themes in cardiovascular ageing, with a separate collection on stroke and atrial fibrillation planned. Treating high blood pressure remains important as people age and reduces strokes and heart attacks. That said, a more personalised approach to blood pressure may be even more important as people age to lower blood pressure to tight targets where appropriate but avoid overtreatment in vulnerable groups. As people age, more people experience blood pressure drops on standing (orthostatic hypotension), particularly as they become frail. This can predispose them to falls. The papers in this collection provide an insight into blood pressure and orthostatic hypotension. They highlight areas for further research to understand blood pressure changes and management in the ageing population. Inpatient clinical care of older people with heart attacks differs from younger people in UK national audit data. People aged over 80 had improved outcomes in survival after heart attack over time, but had lower rates of specialist input from cardiology compared with younger people. This may partly reflect different clinical presentations, with heart attacks occurring in the context of other health conditions, frailty and multimorbidity. The care and outcomes of acute and chronic cardiovascular disease are impacted by the frailty and health status of an individual at baseline. The research included in this collection reinforces the wide variations in the ageing population and the necessity to focus on the individual needs and priorities, and provide a person-centred multidisciplinary approach to care.
    Keywords:  blood pressure; coronary heart disease; hypertension; hypotension; older people; orthostatic
    DOI:  https://doi.org/10.1093/ageing/afac179
  4. Trends Endocrinol Metab. 2022 Aug 08. pii: S1043-2760(22)00140-0. [Epub ahead of print]
      Hexokinase (HK)-1 mitochondrial-binding mechanisms and consequential physiological relevance remain unclear. Recently, De Jesus et al. studied myeloid cells with HK1 carrying mutated mitochondrial-binding domains (MBDs) and provided evidence that HK1 localization controls glucose metabolic fate. Increases in cytosolic HK1 may also contribute to the inflammation associated with diabetes and aging.
    Keywords:  aging; deacetylation; diabetes; glucose metabolism; inflammation; nitrosylation
    DOI:  https://doi.org/10.1016/j.tem.2022.07.005
  5. Blood. 2022 Aug 12. pii: blood.2022016293. [Epub ahead of print]
      The randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial (NCT01757535) evaluated oral azacitidine (Oral-AZA) in patients with AML in first remission after intensive chemotherapy (IC) who were not candidates for hematopoietic stem cell transplant. Eligible patients were randomized 1:1 to Oral-AZA 300 mg or placebo for 14 days/28-day cycle. We evaluated relapse-free (RFS) and overall (OS) survival in patient subgroups defined by NPM1 and FLT3 mutational status at AML diagnosis, and whether survival outcomes in these subgroups were influenced by presence of post-IC measurable residual disease (MRD). Gene mutations at diagnosis were collected from patient case report forms; MRD was determined centrally by multiparameter flow cytometry. Overall, 469 of 472 randomized patients (99.4%) had available mutational data; 137 patients (29.2%) had NPM1mut, 66 (14.1%) had FLT3mut (-ITD and/or -TKDmut), and 30 (6.4%) had NPM1mut/FLT3-ITD at diagnosis. Among patients with NPM1mut, OS and RFS were improved with Oral-AZA by 37% (HR 0.63 [95%CI 0.41-0.98]) and 45% (0.55 [0.35-0.84]), respectively, vs placebo. Median OS was numerically improved with Oral-AZA among NPM1mut patients whether MRD- (48.6 months, vs 31.4 months with placebo) or MRD+ (46.1 vs 10.0 months) post-IC. Among patients with FLT3mut, Oral-AZA improved OS and RFS by 37% (HR 0.63 [95%CI 0.35-1.12]) and 49% (0.51 [0.27-0.95]), respectively, vs placebo. Median OS with Oral-AZA vs placebo was 28.2 vs 16.2 months, respectively, for FLT3mut/MRD- patients, and 24.0 vs 8.0 months for FLT3mut/MRD+ patients. In multivariate analyses, Oral-AZA significantly improved survival independent of NPM1 or FLT3 mutational status, cytogenetic risk, or post-IC MRD status.
    DOI:  https://doi.org/10.1182/blood.2022016293
  6. Aging (Albany NY). 2022 Aug 09. 14(undefined):
      Aging is accompanied by functional loss of many cellular pathways, creating an increased risk of many age-related complications (ARC). Aging causes stem cell exhaustion with a concomitant increase in cellular dysfunction. Recently, interest in senotherapeutics has been growing rapidly to promote healthy aging and as an intervention for ARCs. This research focused on screening the senomorphic properties of Artemisia argyi, as an emerging strategy for longevity, and prevention or treatment of ARCs. In this study, we aimed to find the clinical efficacy of daily consumption of Artemisia argyi water extract (AAW) on aging. In vitro 0.1μM Doxorubicin induced senescent human adipose derived mesenchymal stem cells was treated with different concentrations of AAW to show its anti-aging effect. 15 months old SHR rats (n=6) were treated with 7.9 mg/ml AAW for 4 weeks and anti-aging effect was evaluated. In vitro study showed the protective effect of AAW in telomere shortening and helps in maintaining a balance in the expression of anti-aging protein Klotho and TERT. AAW effectively reduced mitochondrial superoxide and also provided a protective shield against senescence markers like over-expression of p21 and formation of double strand breaks, which is known to cause premature aging. Moreover, animal studies indicated that AAW promoted the expression of Klotho in naturally aging rats. In addition, AAW successfully restored the decline cardiac function and improved the grip strength and memory of aging rat. These findings showed that therapeutic targeting of senescent stem cells by AAW restored stem cell homeostasis and improves overall health.
    Keywords:  Artemisia argyi; anti-aging; antioxidant; klotho; stem cell
    DOI:  https://doi.org/10.18632/aging.204210
  7. Geroscience. 2022 Aug 10.
      Mitochondrial dysfunction is a well-known contributor to aging and age-related diseases. The precise mechanisms through which mitochondria impact human lifespan, however, remain unclear. We hypothesize that humans with exceptional longevity harbor rare variants in nuclear-encoded mitochondrial genes (mitonuclear genes) that confer resistance against age-related mitochondrial dysfunction. Here we report an integrated functional genomics study to identify rare functional variants in ~ 660 mitonuclear candidate genes discovered by target capture sequencing analysis of 496 centenarians and 572 controls of Ashkenazi Jewish descent. We identify and prioritize longevity-associated variants, genes, and mitochondrial pathways that are enriched with rare variants. We provide functional gene variants such as those in MTOR (Y2396Lfs*29), CPS1 (T1406N), and MFN2 (G548*) as well as LRPPRC (S1378G) that is predicted to affect mitochondrial translation. Taken together, our results suggest a functional role for specific mitonuclear genes and pathways in human longevity.
    Keywords:  Aging; Centenarian; Genetic variant; Longevity; Mitochondria
    DOI:  https://doi.org/10.1007/s11357-022-00634-z
  8. Int J Mol Sci. 2022 Aug 06. pii: 8747. [Epub ahead of print]23(15):
      Decreased content and activity of the mechanistic target of rapamycin (mTOR) signalling pathway, as well as the mTOR complex 1 (mTORC1) itself, are key traits for animal species and human longevity. Since mTORC1 acts as a master regulator of intracellular metabolism, it is responsible, at least in part, for the longevous phenotype. Conversely, increased content and activity of mTOR signalling and mTORC1 are hallmarks of ageing. Additionally, constitutive and aberrant activity of mTORC1 is also found in age-related diseases such as Alzheimer's disease (AD) and cancer. The downstream processes regulated through this network are diverse, and depend upon nutrient availability. Hence, multiple nutritional strategies capable of regulating mTORC1 activity and, consequently, delaying the ageing process and the development of age-related diseases, are under continuous study. Among these, the restriction of calories is still the most studied and robust intervention capable of downregulating mTOR signalling and feasible for application in the human population.
    Keywords:  age-related diseases; ageing; longevity; mTORC1; metabolism
    DOI:  https://doi.org/10.3390/ijms23158747
  9. Nutrients. 2022 Jul 28. pii: 3112. [Epub ahead of print]14(15):
      The abnormal expansion of body fat paves the way for several metabolic abnormalities including overweight, obesity, and diabetes, which ultimately cluster under the umbrella of metabolic syndrome (MetS). Patients with MetS are at an increased risk of cardiovascular disease, morbidity, and mortality. The coexistence of distinct metabolic abnormalities is associated with the release of pro-inflammatory adipocytokines, as components of low-to-medium grade systemic inflammation and increased oxidative stress. Adopting healthy lifestyles, by using appropriate dietary regimens, contributes to the prevention and treatment of MetS. Metabolic abnormalities can influence the function and energetic capacity of mitochondria, as observed in many obesity-related cardio-metabolic disorders. There are preclinical studies both in cellular and animal models, as well as clinical studies, dealing with distinct nutrients of the Mediterranean diet (MD) and dysfunctional mitochondria in obesity and MetS. The term "Mitochondria nutrients" has been adopted in recent years, and it depicts the adequate nutrients to keep proper mitochondrial function. Different experimental models show that components of the MD, including polyphenols, plant-derived compounds, and polyunsaturated fatty acids, can improve mitochondrial metabolism, biogenesis, and antioxidant capacity. Such effects are valuable to counteract the mitochondrial dysfunction associated with obesity-related abnormalities and can represent the beneficial feature of polyphenols-enriched olive oil, vegetables, nuts, fish, and plant-based foods, as the main components of the MD. Thus, developing mitochondria-targeting nutrients and natural agents for MetS treatment and/or prevention is a logical strategy to decrease the burden of disease and medications at a later stage. In this comprehensive review, we discuss the effects of the MD and its bioactive components on improving mitochondrial structure and activity.
    Keywords:  Mediterranean diet; metabolic syndrome; mitochondria; obesity; plant-based foods; polyphenols; polyunsaturated fatty acids
    DOI:  https://doi.org/10.3390/nu14153112