bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021–06–13
seven papers selected by
Ayesh Seneviratne, University of Toronto



  1. J Frailty Aging. 2021 ;10(3): 196-201
      The International Conference on Frailty and Sarcopenia Research Task Force met in March 2020, in the shadow of the COVID-19 pandemic, to discuss strategies for advancing the interdisciplinary field of geroscience. Geroscience explores biological mechanisms of aging as targets for intervention that may delay the physiological consequences of aging, maintain function, and prevent frailty and disability. Priorities for clinical practice and research include identifying and validating a range of biomarkers of the hallmarks of aging. Potential biomarkers discussed included markers of mitochondrial dysfunction, proteostasis, stem cell dysfunction, nutrient sensing, genomic instability, telomere dysfunction, cellular senescence, and epigenetic changes. The FRAILOMICS initiative is exploring many of these through various omics studies. Translating this knowledge into new therapies is being addressed by the U.S. National Institute on Aging Translational Gerontology Branch. Research gaps identified by the Task Force include the need for improved cellular and animal models as well as more reliable and sensitive measures.
    Keywords:  Aging; frailty; hallmarks of aging; resilience; translational research
    DOI:  https://doi.org/10.14283/jfa.2021.5
  2. Science. 2021 Jun 08. pii: eabe4832. [Epub ahead of print]
      The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically-ill to SARS-CoV-2-induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells (SnC) become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 Spike protein-1, increasing expression of viral entry proteins and reducing anti-viral gene expression in non-SnCs through a paracrine mechanism. Old mice acutely infected with pathogens that included a SARS-CoV-2-related mouse β-coronavirus experienced increased senescence and inflammation with nearly 100% mortality. Targeting SnCs using senolytic drugs before or after pathogen exposure significantly reduced mortality, cellular senescence, and inflammatory markers and increased anti-viral antibodies. Thus, reducing the SnC burden in diseased or aged individuals should enhance resilience and reduce mortality following viral infection, including SARS-CoV-2.
    DOI:  https://doi.org/10.1126/science.abe4832
  3. Geroscience. 2021 Jun 08.
      Aging and poor nutrition are independent risk factors for the development of chronic disease. When young animals are given diets high in fat or sugar, they exhibit hallmarks of aging like mitochondrial dysfunction and inflammation, and also develop a greater risk for age-related disease. The same mitochondrial dysfunction and inflammation that progress with aging may also further predispose older individuals to dietary insults by fat and sugar. The purpose of this work is to review the most recent studies that address the impact of fat and sugar consumption on hallmarks of aging (mitochondrial dysfunction and inflammation). Findings from these studies show that obesogenic, high-fat diets can exacerbate age-related disease and hallmarks of aging in young animals, but high-fat diets that are non-obesogenic may play a beneficial role in old age. In contrast, high-sugar diets do not require an obesogenic effect to induce mitochondrial dysfunction or inflammation in young rodents. Currently, there is a lack of experimental studies addressing the impact of sugar in the context of aging, even though empirical evidence points to the detrimental effect of sugar in aging by contributing to a variety of age-related diseases. Fig. 1 Mitochondrial dysfunction and altered cellular communication (e.g. inflammation) progress with advancing age and increase the risk for age-related disease (ARD). Given the physiological changes that occur with age, the impact of high-fat (HFD) and high-sugar diets (HSD) may differ in later and earlier stages of life. HFD can promote the development of hallmarks of aging in young animals and can also exacerbate the risk for ARD when consumed at an old age. However, non-obesogenic high-fat diets may also reduce the risk for ARD in old age by acting on these hallmarks of aging. On the other hand, HSD promotes mitochondrial dysfunction and inflammation without necessarily inducing weight gain in young animals. Empirical evidence points to sugar as a major contributor to age-related disease and more experimental studies are needed to clarify whether aged individuals are more susceptible to its effects.
    Keywords:  Fructose; Inflammation; Ketogenic; Mitochondrial dysfunction; Obesity; Old age; Sucrose
    DOI:  https://doi.org/10.1007/s11357-021-00390-6
  4. Aging Cell. 2021 Jun 08. e13415
      Cellular senescence has emerged as a significant and potentially tractable mechanism of aging and multiple aging-related conditions. Biomarkers of senescent cell burden, including molecular signals in circulating immune cells and the abundance of circulating senescence-related proteins, have been associated with chronological age and clinical parameters of biological age in humans. The extent to which senescence biomarkers are affected by interventions that enhance health and function has not yet been examined. Here, we report that a 12-week structured exercise program drives significant improvements in several performance-based and self-reported measures of physical function in older adults. Impressively, the expression of key markers of the senescence program, including p16, p21, cGAS, and TNFα, were significantly lowered in CD3+ T cells in response to the intervention, as were the circulating concentrations of multiple senescence-related proteins. Moreover, partial least squares discriminant analysis showed levels of senescence-related proteins at baseline were predictive of changes in physical function in response to the exercise intervention. Our study provides first-in-human evidence that biomarkers of senescent cell burden are significantly lowered by a structured exercise program and predictive of the adaptive response to exercise.
    Keywords:  aging; immune cells; inflammation; senotherapeutics
    DOI:  https://doi.org/10.1111/acel.13415
  5. JAMA Cardiol. 2021 Jun 09.
       Importance: Clonal hematopoiesis of indeterminate potential (CHIP), the expansion of somatic leukemogenic variations in hematopoietic stem cells, has been associated with atherosclerotic cardiovascular disease. Because the inherited risk of developing CHIP is low, lifestyle elements such as dietary factors may be associated with the development and outcomes of CHIP.
    Objective: To examine whether there is an association between diet quality and the prevalence of CHIP.
    Design, Setting, and Participants: This retrospective cohort study used data from participants in the UK Biobank, an ongoing population-based study in the United Kingdom that examines whole-exome sequencing data and survey-based information on health-associated behaviors. Individuals from the UK Biobank were recruited between 2006 and 2010 and followed up prospectively with linkage to health data records through May 2020. The present study included 44 111 participants in the UK Biobank who were age 40 to 70 years, had data available from whole-exome sequencing of blood DNA, and were free of coronary artery disease (CAD) or hematologic cancer at baseline.
    Exposures: Diet quality was categorized as unhealthy if the intake of healthy elements (fruits and vegetables) was lower than the median of all survey responses, and the intake of unhealthy elements (red meat, processed food, and added salt) was higher than the median. Diets were classified as healthy if the intake of healthy elements was higher than the median, and the intake of unhealthy elements was lower than the median. The presence of CHIP was detected by data from whole-exome sequencing of blood DNA.
    Main Outcomes and Measures: The primary outcome was CHIP prevalence. Multivariable logistic regression analysis was used to examine the association between diet quality and the presence of CHIP. Multivariable Cox proportional hazards models were used to assess the association of incident events (acute coronary syndromes, coronary revascularization, or death) in each diet quality category stratified by the presence of CHIP.
    Results: Among 44 111 participants (mean [SD] age at time of blood sample collection, 56.3 [8.0] years; 24 507 women [55.6%]), 2271 individuals (5.1%) had an unhealthy diet, 38 552 individuals (87.4%) had an intermediate diet, and 3288 individuals (7.5%) had a healthy diet. A total of 2507 individuals (5.7%) had CHIP, and the prevalence of CHIP decreased as diet quality improved from unhealthy (162 of 2271 participants [7.1%]) to intermediate (2177 of 38 552 participants [5.7%]) to healthy (168 of 3288 participants [5.1%]; P = .003 for trend). Compared with individuals without CHIP who had an intermediate diet, the rates of incident cardiovascular events progressively decreased among those with CHIP who had an unhealthy diet (hazard ratio [HR], 1.52; 95% CI, 1.04-2.22) and those with CHIP who had a healthy diet (HR, 0.99; 95% CI, 0.62-1.58) over a median of 10.0 years (interquartile range, 9.6-10.4 years) of follow-up.
    Conclusions and Relevance: This cohort study suggests that an unhealthy diet quality may be associated with a higher prevalence of CHIP and higher rates of adverse cardiovascular events and death independent of CHIP status.
    DOI:  https://doi.org/10.1001/jamacardio.2021.1678
  6. Nat Commun. 2021 06 09. 12(1): 3486
      The metabolome represents a complex network of biological events that reflects the physiologic state of the organism in health and disease. Additionally, specific metabolites and metabolic signaling pathways have been shown to modulate animal ageing, but whether there are convergent mechanisms uniting these processes remains elusive. Here, we used high resolution mass spectrometry to obtain the metabolomic profiles of canonical longevity pathways in C. elegans to identify metabolites regulating life span. By leveraging the metabolomic profiles across pathways, we found that one carbon metabolism and the folate cycle are pervasively regulated in common. We observed similar changes in long-lived mouse models of reduced insulin/IGF signaling. Genetic manipulation of pathway enzymes and supplementation with one carbon metabolites in C. elegans reveal that regulation of the folate cycle represents a shared causal mechanism of longevity and proteoprotection. Such interventions impact the methionine cycle, and reveal methionine restriction as an underlying mechanism. This comparative approach reveals key metabolic nodes to enhance healthy ageing.
    DOI:  https://doi.org/10.1038/s41467-021-23856-9