bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–10–02
seventeen papers selected by
Ayesh Seneviratne, Western University



  1. Cancer Discov. 2022 Sep 28. pii: CD-22-0086. [Epub ahead of print]
      Clonal hematopoiesis resulting from enhanced fitness of mutant hematopoietic stem cells (HSCs) associates with both favorable and unfavorable health outcomes related to the types of mature mutant blood cells produced, but how this lineage output is regulated is unclear. Using a mouse model of a clonal hematopoiesis-associated mutation, DNMT3AR882/+ (Dnmt3aR878H/+), aging-induced TNFα signaling was found to promote the selective advantage of mutant HSCs and stimulate production of mutant B lymphoid cells. Genetic loss of TNFα receptor TNFR1 ablated the selective advantage of mutant HSCs without altering their lineage output, while loss of TNFR2 resulted in overproduction of mutant myeloid cells without altering HSC fitness. These results nominate TNFR1 as a target to reduce clonal hematopoiesis and risk of associated diseases, and support a model wherein clone size and mature blood lineage production can be independently controlled to modulate favorable and unfavorable CH outcomes.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0086
  2. Ageing Res Rev. 2022 Sep 23. pii: S1568-1637(22)00179-9. [Epub ahead of print]81 101737
      Cellular and molecular aging biomarkers might contribute to identify at-risk individuals for frailty before overt clinical manifestations appear. Although studies on the associations of aging biomarkers and frailty exist, no investigation has gathered this information using a structured framework for identifying aging biomarkers; as a result, the evidence on frailty and aging biomarkers is diffuse and incomplete. Therefore, this narrative review aimed to gather information on the associations of the hallmarks of aging and frailty under the perspective of geroscience. The literature on human studies on this topic is sparse and mainly composed of cross-sectional investigations performed in small study samples. The main putative aging biomarkers associated to frailty were: mitochondrial DNA copy number (genomic instability and mitochondrial dysfunction), telomere length (telomere attrition), global DNA methylation (epigenetic alterations), Hsp70 and Hsp72 (loss of proteostasis), IGF-1 and SIRT1 (deregulated nutrient-sensing), GDF-15 (mitochondrial dysfunction, cellular senescence and altered intercellular communication), CD4 + and CD8 + cell percentages (cellular senescence), circulating osteogenic progenitor (COP) cells (stem cell exhaustion), and IL-6, CRP and TNF-alpha (altered intercellular communication). IGF-1, SIRT1, GDF-15, IL-6, CRP and TNF-alpha presented more evidence among these biomarkers, highlighting the importance of inflammation and nutrient sensing on frailty. Further longitudinal studies investigating biomarkers across the hallmarks of aging would provide valuable information on this topic.
    Keywords:  Aging; Biomarkers; Frailty
    DOI:  https://doi.org/10.1016/j.arr.2022.101737
  3. Plast Reconstr Surg. 2022 Oct 01. 150 20S-26S
       SUMMARY: Beyond the palliative reach of today's medicines, medical therapies of tomorrow aim to treat the root cause of age-related diseases by targeting fundamental aging mechanisms. Pillars of aging include, among others, genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, dysregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. The unitary theory of fundamental aging processes posits that by targeting one fundamental aging process, it may be feasible to impact several or all others given its interdependence. Indeed, pathologic accumulation of senescent cells is implicated in chronic diseases and age-associated morbidities, suggesting that senescent cells are a good target for whole-body aging intervention. Preclinical studies using senolytics, agents that selectively eliminate senescent cells, and senomorphics, agents that inhibit production or release of senescence-associated secretory phenotype factors, show promise in several aging and disease preclinical models. Early clinical trials using a senolytic combination (dasatinib and quercetin), and other senolytics including flavonoid, fisetin, and BCL-xL inhibitors, illustrate the potential of senolytics to alleviate age-related dysfunction and diseases including wound healing. Translation into clinical applications requires parallel clinical trials across institutions to validate senotherapeutics as a vanguard for delaying, preventing, or treating age-related disorders and aesthetic aging.
    DOI:  https://doi.org/10.1097/PRS.0000000000009669
  4. Med Clin North Am. 2022 Sep;pii: S0025-7125(22)00058-X. [Epub ahead of print]106(5): 853-863
      Proper nutrition and healthy eating are key determinants of healthy aging. In older age, energy requirements decrease, yet micronutrient requirements stay the same or increase, which make older adults susceptible to nutrient deficiencies. Therefore, it is important to encourage older adults to consume nutrient-dense foods. Many older adults do not maintain proper hydration, so adequate water intake should also be encouraged. Most older adults have multiple chronic diseases that may influence their dietary intake and nutritional needs. However, currently, our understanding of how individual chronic diseases and their associated treatments influence dietary requirements is limited.
    Keywords:  Aging; Dietary requirements; Healthspan; Nutrition
    DOI:  https://doi.org/10.1016/j.mcna.2022.04.008
  5. Aging Cell. 2022 Sep 30. e13718
      Riboflavin is an essential cofactor in many enzymatic processes and in the production of flavin adenine dinucleotide (FAD). Here, we report that the partial depletion of riboflavin through knockdown of the C. elegans riboflavin transporter 1 (rft-1) promotes metabolic health by reducing intracellular flavin concentrations. Knockdown of rft-1 significantly increases lifespan in a manner dependent upon AMP-activated protein kinase (AMPK)/aak-2, the mitochondrial unfolded protein response, and FOXO/daf-16. Riboflavin depletion promotes altered energetic and redox states and increases adiposity, independent of lifespan genetic dependencies. Riboflavin-depleted animals also exhibit the activation of caloric restriction reporters without any reduction in caloric intake. Our findings indicate that riboflavin depletion activates an integrated hormetic response that promotes lifespan and healthspan in C. elegans.
    Keywords:   C. elegans ; rft-1 riboflavin transporter ; AMPK; FOXO; UPRmt; dietary restriction; longevity; riboflavin
    DOI:  https://doi.org/10.1111/acel.13718
  6. Plast Reconstr Surg. 2022 Oct 01. 150 41S-48S
       SUMMARY: The understanding of the molecular and cellular basis of aging has grown exponentially over recent years, and it is now accepted within the scientific community that aging is a malleable process; just as it can be accelerated, it can also be slowed and even reversed. This has far-reaching implications for our attitude and approach toward aging, presenting the opportunity to enter a new era of cellular regenerative medicine to not only manage the external signs of aging but also to develop therapies that support the body to repair and restore itself back to a state of internal well-being. A wealth of evidence now demonstrates that a decline in cellular nicotinamide adenine dinucleotide (NAD+) is a feature of aging and may play a role in the process. NAD+ plays a pivotal role in cellular metabolism and is a co-substrate for enzymes that play key roles in pathways that modify aging. Thus, interventions that increase NAD+ may slow aspects of the aging trajectory, and there is great interest in methods for cellular NAD+ restoration. Given these recent advancements in understanding the cellular aging process, it is important that there is an integration between the basic scientists who are investigating the underlying mechanisms of cellular aging and the surgeons and aesthetic practitioners who are providing antiaging therapies. This will allow the effective translation of this vastly complex area of biology into clinical practice so that people can continue to not only stay looking younger for longer but also experience improved health and wellness.
    DOI:  https://doi.org/10.1097/PRS.0000000000009673
  7. Redox Biol. 2022 Sep 08. pii: S2213-2317(22)00236-1. [Epub ahead of print]57 102464
      Methionine is an essential amino acid, involved in the promotion of growth, immunity, and regulation of energy metabolism. Over the decades, research has long focused on the beneficial effects of methionine supplementation, while data on positive effects of methionine restriction (MR) were first published in 1993. MR is a low-methionine dietary intervention that has been reported to ameliorate aging and aging-related health concomitants and diseases, such as obesity, type 2 diabetes, and cognitive disorders. In addition, MR seems to be an approach to prolong lifespan which has been validated extensively in various animal models, such as Caenorhabditis elegans, Drosophila, yeast, and murine models. MR appears to be associated with a reduction in oxidative stress via so far mainly undiscovered mechanisms, and these changes in redox status appear to be one of the underlying mechanisms for lifespan extension and beneficial health effects. In the present review, the association of methionine metabolism pathways with redox homeostasis is described. In addition, the effects of MR on lifespan, age-related implications, comorbidities, and diseases are discussed.
    Keywords:  Aging; Cognitive disorders; Metabolic syndrome; Methionine restriction; Redox homeostasis
    DOI:  https://doi.org/10.1016/j.redox.2022.102464
  8. J Cachexia Sarcopenia Muscle. 2022 Sep 30.
       BACKGROUND: The Mediterranean diet and other dietary patterns rich in fruits and vegetables have been linked to lower risk of frailty in older adults. However, not all plant-based diets are necessarily healthful, and no previous study has evaluated the role of the quality of plant-based dietary patterns in frailty risk. Our aim was to assess the association between plant-based diet quality and risk of frailty.
    METHODS: Prospective cohort consisted with 82 234 women aged ≥60 years from the Nurses' Health Study, who were followed from 1990 through 2014. The dates of analysis were April 14 to June 23, 2021. Dietary data were collected every 4 years using a validated semi-quantitative food frequency questionnaire. The plant-based diet quality was assessed with two indices (range 18-90 points): (a) healthful plant-based diet index (hPDI), where healthy plant foods (whole grains, fruits, vegetables, nuts, legumes, vegetable oils and tea/coffee) received positive scores, while less healthy plant foods (fruit juices, sweetened beverages, refined grains, potatoes, and sweets/desserts) and animal foods received reverse scores; and (b) unhealthful plant-based diet index (uPDI) where positive scores were given to less healthy plant foods and reverse scores to healthy plant foods and animal foods. Frailty incidence was assessed every 4 years, being defined as having three or more of the following five criteria from the FRAIL scale: fatigue, low strength, reduced aerobic capacity, having ≥5 illnesses and weight loss ≥5%. Multivariable-adjusted Cox proportional-hazards models were used to estimate hazard ratios (HRs) and their 95% confidence interval (CI).
    RESULTS: We identified 12 910 incident cases of frailty over 1 176 401 person-year follow-up. In the multivariable analysis, the hPDI was inversely associated with the risk of frailty (hazard ratio [HR] for the highest vs. lowest quintile: 0.77, 95% confidence interval: 0.72-0.81; P trend <0.001). In addition, a 10-unit increment in the hPDI was associated with a relative 15% lower risk of frailty. Conversely, a direct association was found between the uPDI and risk of frailty (HR highest vs. lowest quintile: 1.24 [1.17, 1.32], P trend <0.001). These associations were consistent for each frailty criterion, among participants with no frailty criteria at baseline, after excluding participants with diabetes, cancer and cardiovascular disease at baseline, for alternative versions of the plant-based diet indices (PDIs), in subgroup analysis by categories of potential confounders, and in latency analysis.
    CONCLUSIONS: A healthful plant-based diet was associated with lower risk of frailty whereas an unhealthful plant-based diet was associated with higher risk.
    Keywords:  cohort study; diet quality; frailty; older adults; plant-based diet
    DOI:  https://doi.org/10.1002/jcsm.13077
  9. Nat Commun. 2022 Sep 27. 13(1): 5671
      Cellular senescence is a plausible mediator of inflammation-related tissue dysfunction. In the aged brain, senescent cell identities and the mechanisms by which they exert adverse influence are unclear. Here we used high-dimensional molecular profiling, coupled with mechanistic experiments, to study the properties of senescent cells in the aged mouse brain. We show that senescence and inflammatory expression profiles increase with age and are brain region- and sex-specific. p16-positive myeloid cells exhibiting senescent and disease-associated activation signatures, including upregulation of chemoattractant factors, accumulate in the aged mouse brain. Senescent brain myeloid cells promote peripheral immune cell chemotaxis in vitro. Activated resident and infiltrating immune cells increase in the aged brain and are partially restored to youthful levels through p16-positive senescent cell clearance in female p16-InkAttac mice, which is associated with preservation of cognitive function. Our study reveals dynamic remodeling of the brain immune cell landscape in aging and suggests senescent cell targeting as a strategy to counter inflammatory changes and cognitive decline.
    DOI:  https://doi.org/10.1038/s41467-022-33226-8
  10. Mol Cell Biol. 2022 Sep 26. e0017122
      Cellular senescence is a stable form of cell cycle arrest associated with proinflammatory responses. Senescent cells can be cleared by the immune system as a part of normal tissue homeostasis. However, senescent cells can also accumulate in aged and diseased tissues, contributing to inflammation and disease progression. The mechanisms mediating the impaired immune-mediated clearance of senescent cells are poorly understood. Here, we report that senescent cells upregulate the immune checkpoint molecule PD-L1, the ligand for PD-1 on immune cells, which drives immune cell inactivation. The induction of PD-L1 in senescence is dependent on the proinflammatory program. Furthermore, the secreted factors released by senescent cells are sufficient to upregulate PD-L1 in nonsenescent control cells, mediated by the JAK-STAT pathway. In addition, we show that prolongevity intervention rapamycin downregulates PD-L1 in senescent cells. Last, we found that PD-L1 is upregulated in several tissues in naturally aged mice and in the lungs of idiopathic pulmonary fibrosis patients. Together, our results report that senescence and aging are associated with upregulation of a major immune checkpoint molecule, PD-L1. Targeting PD-L1 may offer new therapeutic opportunities in treating senescence and age-associated diseases.
    Keywords:  PD-L1; SASP; aging; senescence
    DOI:  https://doi.org/10.1128/mcb.00171-22
  11. Front Psychol. 2022 ;13 998022
      
    Keywords:  aging; frailty; integrated healthcare; lifespan trajectories; multidimensional and dynamic perspective
    DOI:  https://doi.org/10.3389/fpsyg.2022.998022
  12. Front Cell Dev Biol. 2022 ;10 985274
      The prevalence of obesity has dramatically increased worldwide over the past decades. Aging-related chronic conditions, such as type 2 diabetes and cardiovascular disease, are more prevalent in individuals with obesity, thus reducing their lifespan. Epigenetic clocks, the new metrics of biological age based on DNA methylation patterns, could be considered a reflection of the state of one's health. Several environmental exposures and lifestyle factors can induce epigenetic aging accelerations, including obesity, thus leading to an increased risk of age-related diseases. The insight into the complex link between obesity and aging might have significant implications for the promotion of health and the mitigation of future disease risk. The present narrative review takes into account the interaction between epigenetic aging and obesity, suggesting that epigenome may be an intriguing target for age-related physiological changes and that its modification could influence aging and prolong a healthy lifespan. Therefore, we have focused on DNA methylation age as a clinical biomarker, as well as on the potential reversal of epigenetic age using a personalized diet- and lifestyle-based intervention.
    Keywords:  BMI; DNA methylation; DNAm age; epigenetics; lifestyle; obesity
    DOI:  https://doi.org/10.3389/fcell.2022.985274
  13. Nat Commun. 2022 Sep 27. 13(1): 5677
      Fasting exerts beneficial effects in mice and humans, including protection from chemotherapy toxicity. To explore the involved mechanisms, we collect blood from humans and mice before and after 36 or 24 hours of fasting, respectively, and measure lipid composition of erythrocyte membranes, circulating micro RNAs (miRNAs), and RNA expression at peripheral blood mononuclear cells (PBMCs). Fasting coordinately affects the proportion of polyunsaturated versus saturated and monounsaturated fatty acids at the erythrocyte membrane; and reduces the expression of insulin signaling-related genes in PBMCs. When fasted for 24 hours before and 24 hours after administration of oxaliplatin or doxorubicin, mice show a strong protection from toxicity in several tissues. Erythrocyte membrane lipids and PBMC gene expression define two separate groups of individuals that accurately predict a differential protection from chemotherapy toxicity, with important clinical implications. Our results reveal a mechanism of fasting associated with lipid homeostasis, and provide biomarkers of fasting to predict fasting-mediated protection from chemotherapy toxicity.
    DOI:  https://doi.org/10.1038/s41467-022-33352-3