bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021–12–05
twenty papers selected by
Ayesh Seneviratne, University of Toronto



  1. Aging (Albany NY). 2021 Nov 30. 13(undefined):
      The search continues for possible interventions that delay and/or reverse biological aging, resulting in extended healthspan and lifespan. Interventions delaying aging in animal models are well established; however, most lack validation in humans. The length of human lifespan makes it impractical to perform survival analysis. Instead, aging biomarkers, such as DNA methylation (DNAm) clocks, have been developed to monitor biological age. Herein we report a retrospective analysis of DNA methylation age in 42 individuals taking Rejuvant®, an alpha-ketoglutarate based formulation, for an average period of 7 months. DNAm testing was performed at baseline and by the end of treatment with Rejuvant® supplementation. Remarkably, individuals showed an average decrease in biological aging of 8 years (p-value=6.538x10-12). Furthermore, the supplementation with Rejuvant® is robust to individual differences, as indicated by the fact that a large majority of participants decreased their biological age. Moreover, we found that Rejuvant® is of additional benefit to chronologically and biologically older individuals. While continued testing, particularly in a placebo-controlled design, is required, the nearly 8-year reversal in the biological age of individuals taking Rejuvant® for 4 to 10 months is noteworthy, making the natural product cocktail an intriguing candidate to affect human aging.
    Keywords:  DNA methylation; Rejuvant; aging; alpha-ketoglutarate (AKG); biologic age
    DOI:  https://doi.org/10.18632/aging.203736
  2. Plast Reconstr Surg. 2021 Dec 01. 148(6S): 1S-2S
      
    DOI:  https://doi.org/10.1097/PRS.0000000000008777
  3. J Genet Genomics. 2021 Nov 29. pii: S1673-8527(21)00358-1. [Epub ahead of print]
      Maintaining metabolic homeostasis is essential for cellular and organismal health throughout life. Of the multiple signaling pathways that regulate metabolism, such as PI3K/AKT, mTOR, AMPK, and sirtuins, mammalian sirtuins also play unique roles in aging. By understanding how sirtuins regulate metabolic processes, we can start to understand how they slow down or accelerate biological aging. Here, we review the biology of SIRT3, SIRT4, and SIRT5, known as the mitochondrial sirtuins due to their localization in the mitochondrial matrix. First, we will focus on canonical pathways that regulate metabolism more broadly and how these are integrated with aging regulation. Then, we will summarize the current knowledge about functional differences between SIRT3, SIRT4, and SIRT5 in metabolic control and integration in signaling networks. Finally, we will discuss how mitochondrial sirtuins regulate processes associated with aging and oxidative stress, calorie restriction and disease.
    Keywords:  Metabolism and aging regulation; Mitochondrial sirtuins; SIRT3; SIRT4; SIRT5; age-related diseases
    DOI:  https://doi.org/10.1016/j.jgg.2021.11.005
  4. Circulation. 2021 Nov 30. 144(22): 1795-1817
      Nicotinamide adenine dinucleotide (NAD+) is a central metabolite involved in energy and redox homeostasis as well as in DNA repair and protein deacetylation reactions. Pharmacological or genetic inhibition of NAD+-degrading enzymes, external supplementation of NAD+ precursors, and transgenic overexpression of NAD+-generating enzymes have wide positive effects on metabolic health and age-associated diseases. NAD+ pools tend to decline with normal aging, obesity, and hypertension, which are all major risk factors for cardiovascular disease, and NAD+ replenishment extends healthspan, avoids metabolic syndrome, and reduces blood pressure in preclinical models. In addition, experimental elevation of NAD+ improves atherosclerosis, ischemic, diabetic, arrhythmogenic, hypertrophic, or dilated cardiomyopathies, as well as different modalities of heart failure. Here, we critically discuss cardiomyocyte-specific circuitries of NAD+ metabolism, comparatively evaluate distinct NAD+ precursors for their preclinical efficacy, and raise outstanding questions on the optimal design of clinical trials in which NAD+ replenishment or supraphysiological NAD+ elevations are assessed for the prevention or treatment of major cardiac diseases. We surmise that patients with hitherto intractable cardiac diseases such as heart failure with preserved ejection fraction may profit from the administration of NAD+ precursors. The development of such NAD+-centered treatments will rely on technological and conceptual progress on the fine regulation of NAD+ metabolism.
    Keywords:  NAD; cardiomyopathy; heart failure; human; nicotinamide; nicotinamide mononucleotide; obesity
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.121.056589
  5. Ageing Res Rev. 2021 Nov 25. pii: S1568-1637(21)00277-4. [Epub ahead of print]73 101530
       BACKGROUND: Physical frailty and sarcopenia show extensive clinical similarities. Whether biomarkers exist that are shared by the two conditions is presently unclear.
    METHODS: We conducted a systematic review and meta-analysis of cross-sectional and longitudinal studies that investigated the association of frailty and/or sarcopenia with biomarkers as a primary or secondary outcome in adults aged 60 years and older. Only studies published in English that defined frailty using a validated scale and/or questionnaire and diagnosed sarcopenia according to the presence of muscle atrophy plus dynapenia or low physical function were included. Studies were identified from a systematic search of MEDLINE and SCOPUS databases from inception through August 2020. The quality of reporting of each study was assessed by using the Quality Assessment Tool for Observational Cohort, Cross-Sectional and Case-Control studies of the National Institute of Health. A meta-analysis was conducted when at least three studies investigated the same biomarker in both frailty and sarcopenia. Pooled effect size was calculated based on standard mean differences and random-effect models. Sensitivity analysis was performed based on age and the setting where the study was conducted.
    RESULTS: Eighty studies (58 on frailty and 22 on sarcopenia) met the inclusion criteria and were included in the qualitative analysis. Studies on frailty included 33,160 community-dwellers, hospitalized, or institutionalized older adults (60-88 years) from 21 countries. Studies on sarcopenia involved 4904 community-living and institutionalized older adults (68-87.6 years) from 9 countries. Several metabolic, inflammatory, and hematologic markers were found to be shared between the two conditions. Albumin and hemoglobin were negatively associated with both frailty and sarcopenia. Interleukin 6 was associated with frailty and sarcopenia only in people aged < 75. Community-dwelling older adults with frailty and sarcopenia had higher levels of tumor necrosis factor alpha compared with their robust and non-sarcopenic counterparts.
    CONCLUSIONS: A set of metabolic, hematologic, and inflammatory biomarkers was found to be shared by frailty and sarcopenia. These findings fill a knowledge gap in the quest of biomarkers for these conditions and provide a rationale for biomarker selection in studies on frailty and sarcopenia.
    Keywords:  Amino acids; Cytokines; Hematologic markers; Inflammation; Multivariate; Muscle
    DOI:  https://doi.org/10.1016/j.arr.2021.101530
  6. Plast Reconstr Surg. 2021 Dec 01. 148(6S): 7S-13S
       SUMMARY: Aging is a universal feature of life and a complex process at all levels from the biological to the societal. What constitutes older age is subjective and flexible, and how one defines older age is influenced by everchanging individual, generational, and cultural expectations. As the global population ages at an unprecedented rate, we are increasingly confronted with a myriad of challenges associated with aging, including increased healthcare needs and the far-reaching negative consequences of individual and structural agism. However, the shift in world demographics toward an older population is not a growing burden, but an opportunity to reshape our view of older life and proactively embrace healthy aging. Indeed, a healthy person is not defined by the absence of illness, but by the potential for meaningful work, positive relationships, and longevity. Simple preventive measures, such as improved diet and increased exercise, can enhance overall health and quality of life, and growing evidence highlights the potential of positive psychology for improving psychological well-being and overall quality of life. Now more than ever, technological innovation including artificial intelligence can be leveraged to improve our understanding of the causes and consequences of aging, as well as the most effective interventions to enhance resilience and extend healthy longevity. Good health is our greatest asset. It is the responsibility of all-individuals, society, business, science, healthcare systems, and government-to ensure that everyone is well equipped to maintain good health. Together, we can all live better, longer.
    DOI:  https://doi.org/10.1097/PRS.0000000000008780
  7. Ageing Res Rev. 2021 Nov 24. pii: S1568-1637(21)00260-9. [Epub ahead of print]73 101513
      Coronavirus Disease 2019 (COVID-19) is caused by the novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) - the culprit of an ongoing pandemic responsible for the loss of over 3 million lives worldwide within a year and a half. While the majority of SARS-CoV-2 infected people develop no or mild symptoms, some become severely ill and may die from COVID-19-related complications. In this review, we compile and comment on a number of biomarkers that have been identified and are expected to enhance the detection, protection and treatment of individuals at high risk of developing severe illnesses, as well as enable the monitoring of COVID-19 prognosis and responsiveness to therapeutic interventions. Consistent with the emerging notion that the majority of COVID-19 deaths occur in older and frail individuals, we researched the scientific literature and report the identification of a subset of COVID-19 biomarkers indicative of increased vulnerability to developing severe COVID-19 in older and frail patients. Mechanistically, increased frailty results from reduced disease tolerance, a phenomenon aggravated by ageing and comorbidities. While biomarkers of ageing and frailty may predict COVID-19 severity, biomarkers of disease tolerance may predict resistance to COVID-19 with socio-economic factors such as access to adequate health care remaining as major non-biomolecular influencers of COVID-19 outcomes.
    Keywords:  Biomarker; COVID-19; Coronavirus; Disease tolerance; Frailty; SARS-CoV-2
    DOI:  https://doi.org/10.1016/j.arr.2021.101513
  8. Eur J Ageing. 2021 Nov 22. 1-11
      Fears regarding various aspects tend to stimulate individuals to escape or to avoid the sources of the threat. We concluded that fears associated with the future aging process, like the fear of aging-related diseases, the fear of loneliness in old age, and the fear of death, would stimulate patterns of avoidance when it comes to ideal life expectancy. We expected fear of aging-related diseases and fear of loneliness in old age to be related to lower ideal life expectancies. We expected fear of death to be related to higher ideal life expectancies. In two adult lifespan samples [N 1 = 1065 and N 2 = 591; ages ranging from 18 to 95 years, M (SD)1 = 58.1 (17.2) years, M (SD)2 = 52.6 (18.1) years], we were able to support our hypothesis regarding fear of death. We furthermore found significant interactions among the fears, indicating that individuals fearing diseases or loneliness but being unafraid of death opted for the shortest lives. Our results indicate that fears regarding life in very old age might be associated with the wish to avoid this age period; the fear of death was however associated with the wish for particularly long lives, and thus, with distancing oneself from the dreaded event of death. We conclude that fears seem to be associated with how individuals approach old age and with what they wish for in their own future as aged people.
    Keywords:  Aging-related fears; Fear of death; Ideal life expectancy; Longevity desires
    DOI:  https://doi.org/10.1007/s10433-021-00661-3
  9. Adv Gerontol. 2021 ;34(4): 599-608
      From 2017 to the present a scientific project «The use of dermatoprotectors to improve the quality of life of geriatric patients with age-associated xerosis (AAX)» has been realized as part of a typical model of a long-term care system in order to introduce the innovative gerontotechnologies as advanced social practices in further optimization of social and medical care for elderly and senile patients in Leningrad Region. The article presents the results of a comparative analysis of the effectiveness of the dermatoprotectors application in the improvement of the quality of life, prevention and correction of AAX. The AAX clinical manifestations have been studied before and after the emollients use. The cohort under study has included geriatric patients with senile asthenia from seven institutions of social protection of the Leningrad Region. In the foreign literature, such patients are called «fragile». The data thus obtained indicate that AAX as a manifestation of skin «fragility» during aging can be considered as a component of the geriatric syndrome of senile asthenia in patients of older age groups. The development of skin «fragility» significantly reduces the quality of life of geriatric patients and requires timely prevention and correction with adequately selected dermatoprotectors.
    Keywords:  dermatoprotectors; frailty; geriatric patients; gerontotechnology; long-term care system; quality of life; social practices; xerosis
  10. Eur J Nutr. 2021 Nov 30.
    PREDIMED-Plus investigators
       PURPOSE: Long-term nutrition trials may fail to respond to their original hypotheses if participants do not comply with the intended dietary intervention. We aimed to identify baseline factors associated with successful dietary changes towards an energy-reduced Mediterranean diet (MedDiet) in the PREDIMED-Plus randomized trial.
    METHODS: Longitudinal analysis of 2985 participants (Spanish overweight/obese older adults with metabolic syndrome) randomized to the active intervention arm of the PREDIMED-Plus trial. Dietary changes were assessed with a 17-item energy-reduced MedDiet questionnaire after 6 and 12 months of follow-up. Successful compliance was defined as dietary changes from baseline of ≥ 5 points for participants with baseline scores < 13 points or any increase if baseline score was ≥ 13 points. We conducted crude and adjusted multivariable logistic regression models to identify baseline factors related to compliance.
    RESULTS: Consistent factors independently associated with successful dietary change at both 6 and 12 months were high baseline perceived self-efficacy in modifying diet (OR6-month: 1.51, 95% CI 1.25-1.83; OR12-month: 1.66, 95% CI 1.37-2.01), higher baseline fiber intake (OR6-month: 1.62, 95% CI 1.07-2.46; OR12-month: 1.62, 95% CI 1.07-2.45), having > 3 chronic conditions (OR6-month: 0.65, 95% CI 0.53-0.79; OR12-month: 0.76, 95% CI 0.62-0.93), and suffering depression (OR6-month: 0.80, 95% CI 0.64-0.99; OR12-month: 0.71, 95% CI 0.57-0.88).
    CONCLUSION: Our results suggested that recruitment of individuals with high perceived self-efficacy to dietary change, and those who initially follow diets relatively richer in fiber may lead to greater changes in nutritional recommendations. Participants with multiple chronic conditions, specifically depression, should receive specific tailored interventions.
    TRIAL REGISTRATION: ISRCTN registry 89898870, 24th July 2014 retrospectively registered http://www.isrctn.com/ISRCTN89898870 .
    Keywords:  Dietary adherence; Dietary change; Factors; Mediterranean diet; PREDIMED-Plus; Randomized controlled trials
    DOI:  https://doi.org/10.1007/s00394-021-02697-8
  11. Am J Epidemiol. 2021 Dec 01. pii: kwab281. [Epub ahead of print]
      Biological aging is a proposed mechanism through which social determinants drive health disparities. We conducted proof-of-concept testing of eight DNA-methylation and blood-chemistry quantifications of biological aging as mediators of disparities in healthspan between Black and White participants in the 2016 wave of the United States Health and Retirement Study (HRS; n=9005). We quantified biological aging from four DNA-methylation "clocks" (Horvath, Hannum, PhenoAge, and GrimAge), a DNA-methylation Pace of Aging (DunedinPoAm), and three blood-chemistry measures (PhenoAge, Klemera-Doubal method Biological Age, and homeostatic dysregulation). We quantified Black-White disparities in healthspan from cross-sectional and longitudinal data on physical-performance tests, self-reported activities of daily living (ADL) limitations and physician-diagnosed chronic diseases, self-rated health, and survival. DNA-methylation and blood-chemistry quantifications of biological aging were moderately correlated (Pearson-r range 0.1-0.4). GrimAge, DunedinPoAm and all three blood-chemistry measures were associated with healthspan characteristics (e.g. mortality effect-size range HR=1.71-2.32 per SD of biological aging) and showed evidence of more advanced/faster biological aging in Black compared with White participants (Cohen's d=.4-.5). These measures accounted for 13-95% of Black-White differences in healthspan-related characteristics. Findings suggest that reducing disparities in biological aging can contribute to building health equity.
    Keywords:  Biological aging; aging clock; healthy aging; pace of aging; racial disparities
    DOI:  https://doi.org/10.1093/aje/kwab281
  12. Front Immunol. 2021 ;12 738204
      The hematopoietic stem cell (HSC) niche is a specialized microenvironment, where a complex and dynamic network of interactions across multiple cell types regulates HSC function. During the last years, it became progressively clearer that changes in the HSC niche are responsible for specific alterations of HSC behavior. The aging of the bone marrow (BM) microenvironment has been shown to critically contribute to the decline in HSC function over time. Interestingly, while upon aging some niche structures within the BM are degenerated and negatively affect HSC functionality, other niche cells and specific signals are preserved and essential to retaining HSC function and regenerative capacity. These new findings on the role of the aging BM niche critically depend on the implementation of new technical tools, developed thanks to transdisciplinary approaches, which bring together different scientific fields. For example, the development of specific mouse models in addition to coculture systems, new 3D-imaging tools, ossicles, and ex-vivo BM mimicking systems is highlighting the importance of new technologies to unravel the complexity of the BM niche on aging. Of note, an exponential impact in the understanding of this biological system has been recently brought by single-cell sequencing techniques, spatial transcriptomics, and implementation of artificial intelligence and deep learning approaches to data analysis and integration. This review focuses on how the aging of the BM niche affects HSCs and on the new tools to investigate the specific alterations occurring in the BM upon aging. All these new advances in the understanding of the BM niche and its regulatory function on HSCs have the potential to lead to novel therapeutical approaches to preserve HSC function upon aging and disease.
    Keywords:  HSC niche; aging; arteriolar niche; bone marrow imaging; deep learning; sinusoidal niche; vessel remodeling
    DOI:  https://doi.org/10.3389/fimmu.2021.738204
  13. Cardiovasc Hematol Disord Drug Targets. 2021 Nov 30.
      Cardiovascular disease continues to rise at an alarming rate, and research focuses on possible therapies to reduce the risk and slow down its progression. Several epidemiological studies have indicated that dietary modifications, such as increased consumption of fruits and vegetables play an important role in reducing cardiovascular disease risk factors. Food sources rich in antioxidants, anti-inflammatory, hypolipidemic, and hypoglycemic properties are thought to ameliorate the progression of cardiovascular disease and serve as a potential treatment mode. Many in vivo and in vitro studies using turmeric, cinnamon, mango, blueberries, red wine, chocolate, and extra virgin olive oil have demonstrated significant improvements in cholesterol profiles, toxic reactive oxygen species, inflammation, obesity, and hypertension. In this review, we summarize recent evidence on the cardioprotective effect of different food groups, outline their potential mechanisms involved in slowing down the progression of cardiovascular disease, and highlight the beneficial effects associated with increased consumption.
    Keywords:  Nutraceuticals; antioxidants; atherosclerosis; cardiovascular disease (CVD); coronary artery disease (CAD); dyslipidemia; oxidative stress
    DOI:  https://doi.org/10.2174/1871529X21666211201104124
  14. Curr Atheroscler Rep. 2021 Dec 01. 23(12): 80
       PURPOSE OF REVIEW: Chronic inflammation has been recognized as one of the most important pathophysiological mechanisms' initiation and progression of atherosclerosis. Statins belong to most successful therapeutic agents in the prevention and treatment of atherothrombotic vascular disease. Their non-lipid related effects including suppression of inflammation have been repeatedly proven in both experimental and clinical settings.
    RECENT FINDINGS: Recently, the importance of inflammation in the process of atherosclerosis has been confirmed by interventions targeting inflammation selectively. Clinical trial with selective inhibitor of a principal inflammatory mediator interleukin 1-beta - canakinumab - confirmed the notion of direct vasculoprotective effects of primarily targeting inflammation. This has increased interest in the non-lipid, pleiotropic and, particularly, anti-inflammatory effects of statins. Anti-inflammatory effects of statins have been proven both experimentally and in clinical settings beyond any doubt. They comprise a direct positive effect on not only many cell types and pathways that are lipid independent but, also, some that are mediated by lipid modification. Undoubtedly, suppression of inflammatory response by statins contributes to their generally positive action in atherosclerosis and represents an important part of the vasculo- and atheroprotective effect of this drug class.
    Keywords:  Atherosclerosis; Biomarkers; Cardiovascular; Endothelial function; Inflammation; Pleiotropy; Statins
    DOI:  https://doi.org/10.1007/s11883-021-00977-6
  15. Front Genet. 2021 ;12 742095
      Functional foods are natural products of plants that have health benefits beyond necessary nutrition. Functional foods are abundant in fruits, vegetables, spices, beverages and some are found in cereals, millets, pulses and oilseeds. Efforts to identify functional foods in our diet and their beneficial aspects are limited to few crops. Advances in sequencing and availability of different omics technologies have given opportunity to utilize these tools to enhance the functional components of the foods, thus ensuring the nutritional security. Integrated omics approaches including genomics, transcriptomics, proteomics, metabolomics coupled with artificial intelligence and machine learning approaches can be used to improve the crops. This review provides insights into omics studies that are carried out to find the active components and crop improvement by enhancing the functional compounds in different plants including cereals, millets, pulses, oilseeds, fruits, vegetables, spices, beverages and medicinal plants. There is a need to characterize functional foods that are being used in traditional medicines, as well as utilization of this knowledge to improve the staple foods in order to tackle malnutrition and hunger more effectively.
    Keywords:  functional foods; genomics; nutraceuticals; nutrition; transgene
    DOI:  https://doi.org/10.3389/fgene.2021.742095
  16. Aging Clin Exp Res. 2021 Nov 29.
       BACKGROUND: Social relationships play a fundamental role in individuals' lives and health, and social isolation is prevalent among older people. Chronic non-communicable diseases (NCDs) and frailty are also common in older adults.
    AIMS: To examine the association between number of NCDs and social isolation in a cohort of community-dwelling older adults in the UK, and to consider whether any potential association is mediated by frailty.
    METHODS: NCDs were self-reported by 176 older community-dwelling UK adults via questionnaire. Social isolation was assessed using the six-item Lubben Social Network Scale. Frailty was assessed by the Fried phenotype of physical frailty.
    RESULTS: The median (IQR) age of participants in this study was 83.1 (81.5-85.5) years for men and 83.8 (81.5-85.9) years for women. The proportion of socially isolated individuals was 19% in men and 20% in women. More women (18%) than men (13%) were identified as frail. The number of NCDs was associated with higher odds of being isolated in women (unadjusted odds ratio per additional NCD: 1.65, 95% CI 1.08, 2.52, p = 0.021), but not in men, and the association remained robust to adjustment, even when accounting for frailty (OR 1.85, 95% CI 1.06, 3.22, p = 0.031).
    DISCUSSION: Number of self-reported NCDs was associated with higher odds of social isolation in women but not in men, and the association remained after considering frailty status.
    CONCLUSIONS: Our observations may be considered by healthcare professionals caring for community-dwelling older adults with multiple NCDs, where enquiring about social isolation as part of a comprehensive assessment may be important.
    Keywords:  Ageing; Frailty; Multimorbidity; Non-communicable diseases; Older people; Social Isolation
    DOI:  https://doi.org/10.1007/s40520-021-02026-3
  17. Eur J Cardiothorac Surg. 2021 Nov 29. pii: ezab505. [Epub ahead of print]
      
    Keywords:  Local gentamicin; Randomized controlled trial; Sternal wound infection
    DOI:  https://doi.org/10.1093/ejcts/ezab505
  18. Biochimie. 2021 Nov 24. pii: S0300-9084(21)00271-6. [Epub ahead of print]
      AMPK is an important kinase regulating energy homeostasis and also a key protein involved in a variety of signal transduction pathways. It plays a vitally regulatory role in cellular senescence. Activation of AMPK can delay or block the aging process, which is of great significance in the treatment of cardiovascular diseases and other aging related diseases, and provides a potential target for new indications such as Alzheimer's disease. Therefore, AMPK signaling pathway plays an important role in aging research. The in-depth study of AMPK activators will provide more new directions for the treatment of age-related maladies and the development of innovative drugs. Autophagy is a process that engulfs and degrades own cytoplasm or organelles. Thereby, meeting the metabolic demands and updating certain organelles of the cell has become a hotspot in the field of anti-aging in recent years. AMPK plays an important role between autophagy and senescence. In our review, the relationship among AMPK signaling, autophagy and aging will be clarified through the interaction between AMPK and mTOR, ULK1, FOXO, p53, SIRT1, and NF -κB.
    Keywords:  AMPK; Aging; Autophagy; Disease; Signaling pathways
    DOI:  https://doi.org/10.1016/j.biochi.2021.11.008