bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–12–18
eightteen papers selected by
Ayesh Seneviratne, Western University
  1. Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin.
  2. Aging and aging-related diseases: from molecular mechanisms to interventions and treatments.
  3. Trajectories, transitions and trends in frailty among older adults: a review.
  4. Nutraceuticals and their role in promoting musculoskeletal healthy aging.
  5. Importance of NAD+ Anabolism in Metabolic, Cardiovascular and Neurodegenerative Disorders.
  6. A low carbohydrate diet high in fish oil and soy protein delays inflammation, hematopoietic stem cell depletion, and mortality in miR-146a knock-out mice.
  7. Myeloid cells promote interferon signaling-associated deterioration of the hematopoietic system.
  8. Splicing factor deficits render hematopoietic stem and progenitor cells sensitive to STAT3 inhibition.
  9. Relationship between specific leisure activities and successful aging among older adults.
  10. The Physician's Role in Transitioning Older Adults Into Long-term Care Facilities.
  11. Targeting AMPK signaling by polyphenols: a novel strategy for tackling aging.
  12. The DARC Side of Inflamm-Aging: Duffy Antigen Receptor for Chemokines (DARC/ACKR1) as a Potential Biomarker of Aging, Immunosenescence, and Breast Oncogenesis among High-Risk Subpopulations.
  13. AML-derived extracellular vesicles negatively regulate stem cell pool size: A step toward bone marrow failure.
  14. The Role of Exercise-Induced Reactive Oxygen Species (ROS) Hormesis in Aging: Friend or Foe.
  15. Immunosenescence and inflamm-ageing in COVID-19.
  16. Nutraceutical activation of Sirt1: a review.
  17. Prefrailty subtypes differentially predict 5-year mortality in the functionally independent geriatric population.
  18. Aging-associated HELIOS deficiency in naive CD4+ T cells alters chromatin remodeling and promotes effector cell responses.
  1. Aging Cell. 2022 Dec 14. e13754
    Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin.
    Michael Vreones, Maja Mustapic, Ruin Moaddel, Krishna A Pucha, Jacqueline Lovett, Douglas R Seals, Dimitrios Kapogiannis, Christopher R Martens.
      Declining nicotinamide adenine dinucleotide (NAD+ ) concentration in the brain during aging contributes to metabolic and cellular dysfunction and is implicated in the pathogenesis of aging-associated neurological disorders. Experimental therapies aimed at boosting brain NAD+ levels normalize several neurodegenerative phenotypes in animal models, motivating their clinical translation. Dietary intake of NAD+ precursors, such as nicotinamide riboside (NR), is a safe and effective avenue for augmenting NAD+ levels in peripheral tissues in humans, yet evidence supporting their ability to raise NAD+ levels in the brain or engage neurodegenerative disease pathways is lacking. Here, we studied biomarkers in plasma extracellular vesicles enriched for neuronal origin (NEVs) from 22 healthy older adults who participated in a randomized, placebo-controlled crossover trial (NCT02921659) of oral NR supplementation (500 mg, 2x /day, 6 weeks). We demonstrate that oral NR supplementation increases NAD+ levels in NEVs and decreases NEV levels of Aβ42, pJNK, and pERK1/2 (kinases involved in insulin resistance and neuroinflammatory pathways). In addition, changes in NAD(H) correlated with changes in canonical insulin-Akt signaling proteins and changes in pERK1/2 and pJNK. These findings support the ability of orally administered NR to augment neuronal NAD+ levels and modify biomarkers related to neurodegenerative pathology in humans. Furthermore, NEVs offer a new blood-based window into monitoring the physiologic response of NR in the brain.
    Keywords:  NAD+; NADH; extracellular vesicles; neurodegenerative disease
    DOI:  https://doi.org/10.1111/acel.13754
  2. Signal Transduct Target Ther. 2022 Dec 16. 7(1): 391
    Aging and aging-related diseases: from molecular mechanisms to interventions and treatments.
    Jun Guo, Xiuqing Huang, Lin Dou, Mingjing Yan, Tao Shen, Weiqing Tang, Jian Li.
      Aging is a gradual and irreversible pathophysiological process. It presents with declines in tissue and cell functions and significant increases in the risks of various aging-related diseases, including neurodegenerative diseases, cardiovascular diseases, metabolic diseases, musculoskeletal diseases, and immune system diseases. Although the development of modern medicine has promoted human health and greatly extended life expectancy, with the aging of society, a variety of chronic diseases have gradually become the most important causes of disability and death in elderly individuals. Current research on aging focuses on elucidating how various endogenous and exogenous stresses (such as genomic instability, telomere dysfunction, epigenetic alterations, loss of proteostasis, compromise of autophagy, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, deregulated nutrient sensing) participate in the regulation of aging. Furthermore, thorough research on the pathogenesis of aging to identify interventions that promote health and longevity (such as caloric restriction, microbiota transplantation, and nutritional intervention) and clinical treatment methods for aging-related diseases (depletion of senescent cells, stem cell therapy, antioxidative and anti-inflammatory treatments, and hormone replacement therapy) could decrease the incidence and development of aging-related diseases and in turn promote healthy aging and longevity.
    DOI:  https://doi.org/10.1038/s41392-022-01251-0
  3. Ann Geriatr Med Res. 2022 Dec 12.
    Trajectories, transitions and trends in frailty among older adults: a review.
    Emiel O Hoogendijk, Elsa Dent.
      Frailty is an age-related clinical state associated with deterioration across multiple physiological systems and a leading cause of morbidity and mortality later in life. To understand how frailty develops and what causes its progression, longitudinal data with repeated frailty measurements are required. This review summarizes evidence from longitudinal studies on frailty trajectories, transitions, and trends. We identified several consistent findings: frailty increases with aging and is a dynamic condition, and more recent generations of older adults have higher frailty levels. These findings have both clinical and public health relevance, including the provision of health- and aged care services in the coming years. Further studies are required, particularly those conducted in low- and middle-income countries and those investigating factors associated with changes in frailty. The latter may help develop better-targeted interventions to reverse or slow the progression of frailty.
    Keywords:  aging; frail older adults; frailty; longitudinal studies; trends
    DOI:  https://doi.org/10.4235/agmr.22.0148
  4. Ann Ig. 2022 Dec 15.
    Nutraceuticals and their role in promoting musculoskeletal healthy aging.
    T A Alalwan.
       Background: Aging is a complex and gradual biological process that represents the major risk factor with respect to the development of chronic degenerative diseases, often associated with disability. Diet and nutrition, coupled with proper physical activity have a significant impact on the health status of the elderly with a decreased risk of disease being indicative of successful aging. Musculoskeletal conditions such as osteoporosis and sarcopenia are the most frequently reported disorders among the elderly community.
    Methods: This study presents a systematic review of the literature on the potential benefits of several nutraceuticals in promoting healthy aging and in reducing the risk of chronic diseases in elderly individuals.
    Results: Dietary components including vitamins (vitamin C, B vitamin and vitamin K) flavonoids (e.g., quercetin, anthocyanins, and isoflavones), minerals (e.g., magnesium, zinc and potassium) and other nutrients such phytoestrogens, amino acids, and omega-3 fatty acids help in slowing the aging process, which ultimately results in increased lifespan and longevity.
    Conclusions: This paper highlights the key nutrients and phytochemicals of nutraceutical importance for the healthy aging of the elderly population. Although the scientific literature provides evidences of therapeutic effectiveness of nutraceuticals, more in-depth clinical investigations are needed.
    Keywords:  Healthy aging; antioxidants; inflammation; nutraceuticals; osteoporosis; sarcopenia
    DOI:  https://doi.org/10.7416/ai.2022.2552
  5. Drugs Aging. 2022 Dec 13.
    Importance of NAD+ Anabolism in Metabolic, Cardiovascular and Neurodegenerative Disorders.
    Tessa Helman, Nady Braidy.
      The role of nicotinamide adenine dinucleotide (NAD+) in ageing has emerged as a critical factor in understanding links to a wide range of chronic diseases. Depletion of NAD+, a central redox cofactor and substrate of numerous metabolic enzymes, has been detected in many major age-related diseases. However, the mechanisms behind age-associated NAD+ decline remains poorly understood. Despite limited conclusive evidence, supplements aimed at increasing NAD+ levels are becoming increasingly popular. This review provides renewed insights regarding the clinical utility and benefits of NAD+ precursors, namely nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), in attenuating NAD+ decline and phenotypic characterization of age-related disorders, including metabolic, cardiovascular and neurodegenerative diseases. While it is anticipated that NAD+ precursors can play beneficial protective roles in several conditions, they vary in their ability to promote NAD+ anabolism with differing adverse effects. Careful evaluation of the role of NAD+, whether friend or foe in ageing, should be considered.
    DOI:  https://doi.org/10.1007/s40266-022-00989-0
  6. Front Nutr. 2022 ;9 1017347
    A low carbohydrate diet high in fish oil and soy protein delays inflammation, hematopoietic stem cell depletion, and mortality in miR-146a knock-out mice.
    Ingrid Elisia, Sara Kowalski, Michelle Yeung, Jennifer Wong, Jennifer M Grants, Aly Karsan, Gerald Krystal.
      Since our previous studies found a low carbohydrate (CHO) diet containing soy protein and fish oil (15%Amylose/Soy/FO) significantly reduced lung and breast cancer in mice we asked herein if this low CHO diet could also delay the onset of myeloid malignancies. To test this we employed a miR-146a knock-out (KO) mouse model and found the 15%Amylose/Soy/FO diet increased their median lifespan by 8.5 month, compared to these mice on a Western diet. This was associated with increased lymphocytes and reduced monocytes, granulocytes, blood glucose and insulin levels. Inflammatory cytokine/chemokine studies carried out with 6-month-old mice, before any signs of illness, revealed the 15%Amylose/Soy/FO diet significantly reduced pro-inflammatory cytokines. This low CHO diet also led to an increase in plasma β-hydroxybutyrate and in liver fatty acid synthase levels. This, together with higher liver carnitine palmitoyltransferase I levels suggested that the 15%Amylose/Soy/FO diet was causing a systemic metabolic shift from glucose to fatty acids as an energy source. Lastly, we found the 15%Amylose/Soy/FO diet resulted in significantly higher numbers of primitive hematopoietic stem cells (HSCs) in the bone marrow of 6-month-old mice than those fed a Western diet. Taken together, these results suggest a 15%Amylose/Soy/FO diet reduces chronic inflammation and increases fatty acid oxidation and that this, in turn, may prevent HSC proliferation and exhaustion, thereby delaying myeloid malignancy-induced death of miR-146a KO mice. We suggest a low CHO diet containing soy protein and fish oil could be beneficial in reducing the risk of myeloid malignancies in patients with low miR-146a levels.
    Keywords:  HSC exhaustion; inflammation; low carbohydrate diet; miR-146a; stem cell
    DOI:  https://doi.org/10.3389/fnut.2022.1017347
  7. Nat Commun. 2022 Dec 10. 13(1): 7657
    Myeloid cells promote interferon signaling-associated deterioration of the hematopoietic system.
    Jacqueline Feyen, Zhen Ping, Lanpeng Chen, Claire van Dijk, Tim V D van Tienhoven, Paulina M H van Strien, Remco M Hoogenboezem, Michiel J W Wevers, Mathijs A Sanders, Ivo P Touw, Marc H G P Raaijmakers.
      Innate and adaptive immune cells participate in the homeostatic regulation of hematopoietic stem cells (HSCs). Here, we interrogate the contribution of myeloid cells, the most abundant cell type in the mammalian bone marrow, in a clinically relevant mouse model of neutropenia. Long-term genetic depletion of neutrophils and eosinophils results in activation of multipotent progenitors but preservation of HSCs. Depletion of myeloid cells abrogates HSC expansion, loss of serial repopulation and lymphoid reconstitution capacity and remodeling of HSC niches, features previously associated with hematopoietic aging. This is associated with mitigation of interferon signaling in both HSCs and their niches via reduction of NK cell number and activation. These data implicate myeloid cells in the functional decline of hematopoiesis, associated with activation of interferon signaling via a putative neutrophil-NK cell axis. Innate immunity may thus come at the cost of system deterioration through enhanced chronic inflammatory signaling to stem cells and their niches.
    DOI:  https://doi.org/10.1038/s41467-022-35318-x
  8. Cell Rep. 2022 Dec 13. pii: S2211-1247(22)01717-X. [Epub ahead of print]41(11): 111825
    Splicing factor deficits render hematopoietic stem and progenitor cells sensitive to STAT3 inhibition.
    Kathryn S Potts, Rosannah C Cameron, Amina Metidji, Noura Ghazale, LaShanale Wallace, Ana I Leal-Cervantes, Reid Palumbo, Juan Martin Barajas, Varun Gupta, Srinivas Aluri, Kith Pradhan, Jacquelyn A Myers, Mia McKinstry, Xiaoying Bai, Gaurav S Choudhary, Aditi Shastri, Amit Verma, Esther A Obeng, Teresa V Bowman.
      Hematopoietic stem and progenitor cells (HSPCs) sustain lifelong hematopoiesis. Mutations of pre-mRNA splicing machinery, especially splicing factor 3b, subunit 1 (SF3B1), are early lesions found in malignancies arising from HSPC dysfunction. However, why splicing factor deficits contribute to HSPC defects remains incompletely understood. Using zebrafish, we show that HSPC formation in sf3b1 homozygous mutants is dependent on STAT3 activation. Clinically, mutations in SF3B1 are heterozygous; thus, we explored if targeting STAT3 could be a vulnerability in these cells. We show that SF3B1 heterozygosity confers heightened sensitivity to STAT3 inhibition in zebrafish, mouse, and human HSPCs. Cells carrying mutations in other splicing factors or treated with splicing modulators are also more sensitive to STAT3 inhibition. Mechanistically, we illustrate that STAT3 inhibition exacerbates aberrant splicing in SF3B1 mutant cells. Our findings reveal a conserved vulnerability of splicing factor mutant HSPCs that could allow for their selective targeting in hematologic malignancies.
    Keywords:  CP: Molecular biology; CP: Stem cell research; SF3B1; STAT3; hematopoietic stem and progenitor cell; myelodysplastic syndrome; splicing factor; zebrafish
    DOI:  https://doi.org/10.1016/j.celrep.2022.111825
  9. J Exerc Sci Fit. 2023 Jan;21(1): 111-118
    Relationship between specific leisure activities and successful aging among older adults.
    Xiaoguang Zhao, Jiabin Yu, Nan Liu.
       Background/Objectives: This study was designed to investigate the association between specific leisure activities and successful aging among older adults, using data from the Chinese Longitudinal Healthy Longevity Survey.
    Methods: A total of 7689 older adults were involved in this study and categorized as successful aging group (n = 3989; 51.8%) or non-successful aging group (n = 3703; 48.2%). Participants were identified as successful aging if they had a score of more than 3 points, or as non-successful aging. The points were based on the following five items and each item was assigned 1 point: self-rated health, self-rated psychological status or mood, cognitive function, activities of daily life, and physical activity. Six activities including gardening work, reading newspapers or books, raising domestic animals or pets, playing cards or mahjong, watching TV or listening to radio, and participating in social activities were collected to reflect leisure activities. Chi-square tests, independent sample t-test, and logistic regression analyses were employed to explore the association between specific leisure activities and successful aging.
    Results: The prevalence of successful aging was 51.8% among Chinese older adults. A significant positive relationship was found between the frequency of participation in specific leisure activities and successful aging (p < 0.05). Older adults who usually participated in leisure activities had greater odds for successful aging compared to those who never participated in leisure activities (adjusted odds ratio (OR): 1.31 (95% CI: 1.15-1.49) to 1.88 (95% CI: 1.62-2.19)). Older adults participating in one or more leisure activities had greater odds for successful aging compared to those who did not participate in leisure activities (adjusted OR: 1.51 (95% CI: 1.30-1.76) to 4.10 (95% CI: 2.44-6.89)).
    Conclusions: The findings provide evidence that participating more frequently and in more leisure activities was associated with a greater probability of successful aging among Chinese older adults. Encouraging older people to participate frequently in a larger number of leisure activities may be a key to promote successful aging. Therefore, the frequency and number of participation in leisure activities should be highlighted and targeted for promoting successful aging.
    Keywords:  Aging process; Cognitive function; Older adults; Physical activity; Population aging
    DOI:  https://doi.org/10.1016/j.jesf.2022.11.006
  10. Am Fam Physician. 2022 Dec;106(6): 714-717
    The Physician's Role in Transitioning Older Adults Into Long-term Care Facilities.
    Brian K Unwin, Nicole Bailey Bedsaul, Sarah Stubbs.
      
  11. Food Funct. 2022 Dec 16.
    Targeting AMPK signaling by polyphenols: a novel strategy for tackling aging.
    Wei Xu, Yi Luo, Jiaxin Yin, Mengzhen Huang, Feijun Luo.
      Aging is an inevitable biological process and is accompanied by a gradual decline of physiological functions, such as the incidence of age-related diseases. Aging becomes a major burden and challenge for society to prevent or delay the occurrence and development of these age-related diseases. AMPK is a key regulator of intracellular energy and participates in the adaptation of calorie restriction. It is also an important mediator of nutritionally sensitive pathways that regulate the biological effects of nutrient active ingredients. AMPK can limit proliferation and activate autophagy. Recent studies have shown that nutritional intervention can delay aging and lessen age-related diseases in many animal and even human models. Polyphenols function as a natural antidote and are important anti-inflammatory and antioxidant agents in human diets. Polyphenols can prevent age-related diseases because they regulate complex networks of cellular processes such as oxidative damage, inflammation, cellular aging, and autophagy, and have also attracted wide attention as a potential beneficial substance for longevity. In this review, we systemically summarized the progress of targeting AMPK signaling by dietary polyphenols in aging prevention. Polyphenols can reduce oxidative stress and inflammatory response, and maintain the steady state of energy. Polyphenols can also modulate sirtuins/NAD+, nutrient-sensing, proteostasis, mitochondrial function, autophagy and senescence via targeting AMPK signaling. Therefore, targeting the AMPK signaling pathway by dietary polyphenols may be a novel anti-aging strategy.
    DOI:  https://doi.org/10.1039/d2fo02688k
  12. Cells. 2022 Nov 29. pii: 3818. [Epub ahead of print]11(23):
    The DARC Side of Inflamm-Aging: Duffy Antigen Receptor for Chemokines (DARC/ACKR1) as a Potential Biomarker of Aging, Immunosenescence, and Breast Oncogenesis among High-Risk Subpopulations.
    Nikita Jinna, Padmashree Rida, Tianyi Su, Zhihong Gong, Song Yao, Mark LaBarge, Rama Natarajan, Tijana Jovanovic-Talisman, Christine Ambrosone, Victoria Seewaldt.
      The proclivity of certain pre-malignant and pre-invasive breast lesions to progress while others do not continues to perplex clinicians. Clinicians remain at a crossroads with effectively managing the high-risk patient subpopulation owing to the paucity of biomarkers that can adequately risk-stratify and inform clinical decisions that circumvent unnecessary administration of cytotoxic and invasive treatments. The immune system mounts the most important line of defense against tumorigenesis and progression. Unfortunately, this defense declines or "ages" over time-a phenomenon known as immunosenescence. This results in "inflamm-aging" or the excessive infiltration of pro-inflammatory chemokines, which alters the leukocyte composition of the tissue microenvironment, and concomitant immunoediting of these leukocytes to diminish their antitumor immune functions. Collectively, these effects can foster the sequelae of neoplastic transformation and progression. The erythrocyte cell antigen, Duffy antigen receptor for chemokines(DARC/ACKR1), binds and internalizes chemokines to maintain homeostatic levels and modulate leukocyte trafficking. A negative DARC status is highly prevalent among subpopulations of West African genetic ancestry, who are at higher risk of developing breast cancer and disease progression at a younger age. However, the role of DARC in accelerated inflamm-aging and malignant transformation remains underexplored. Herein, we review compelling evidence suggesting that DARC may be protective against inflamm-aging and, therefore, reduce the risk of a high-risk lesion progressing to malignancy. We also discuss evidence supporting that immunotherapeutic intervention-based on DARC status-among high-risk subpopulations may evade malignant transformation and progression. A closer look into this unique role of DARC could glean deeper insight into the immune response profile of individual high-risk patients and their predisposition to progress as well as guide the administration of more "cyto-friendly" immunotherapeutic intervention to potentially "turn back the clock" on inflamm-aging-mediated oncogenesis and progression.
    Keywords:  breast cancer; duffy antigen receptor for chemokines; duffy null allele; high-risk; immunosenescence; inflamm-aging; oncogenesis
    DOI:  https://doi.org/10.3390/cells11233818
  13. Curr Res Transl Med. 2022 Nov 30. pii: S2452-3186(22)00043-5. [Epub ahead of print]71(1): 103375
    AML-derived extracellular vesicles negatively regulate stem cell pool size: A step toward bone marrow failure.
    Bahrampour Shahrokh, Farsani Mehdi Allahbakhshian, Gharehbaghian Ahmad, Feizi Fatemeh, Mohammadi Mohammad Hossein.
       PURPOSE OF THE STUDY: Long-term repopulating hematopoietic stem cells (LTR-HSCs) have been previously shown to reside in close proximity to osteoblasts, where they take shelter in the bone marrow (BM) microenvironment against cytotoxic and apoptotic stimuli. Nevertheless, the function of the HSC niche is believed to undergo an adaptive evolutionary modification during leukemogenesis. Recent studies have demonstrated that leukemic clones can impact BM homing through extracellular vesicle (EV) secretion. However, the exact mechanism driving BM conversion is still unclear. In the present study, the human osteoblast cell line (MG-63) were subjected to various concentration of sera-derived EVs of patients with acute myeloid leukemia (AML) and healthy volunteers to assess if they are associated strongly enough to alter the expression pattern of cross-talk molecules involved in niche interactions.
    METHOD: To gain a brief insight into the EVs secretion criteria, we first conducted a comparative analysis of sera-derived EVs by dynamic light scattering (DLS), transmission electron microscopy (TEM), and Bradford assay. After incubating MG-63 cell lines with increasing concentrations of the EVs, Trypan-blue and microculture tetrazolium test (MTT) assays were used to evaluate the cell survival, logarithmic growth, and metabolic activity. Finally, the expression levels of OPN, ANGPT-1, and JAG-1 transcripts were evaluated through the qRT-PCR technique.
    RESULTS: Here, we report that AML-derived EVs can affect the viability, cell growth, and metabolic activity of the human osteoblasts cell line (MG-63) compared to those that received healthy-derived EVs. We also found that leukemic EVs tend to induce overexpression of OPN but reduce the expression of ANGPT-1 and JAG-1 genes in the osteoblast transcriptome, which may provide a potential context imposing selective suppression of HSC pool size.
    CONCLUSION: These findings extend the general concept of a novel mechanism in which leukemic EVs would make it possible to create a specialized pre-metastatic microenvironment in the interest of tumor expansion, allowing leukemic clones to overcome their HSCs counterparts.
    Keywords:  Acute myeloid leukemia; Cell adhesion molecule; Extracellular vesicles; Hematopoiesis; Osteoblast
    DOI:  https://doi.org/10.1016/j.retram.2022.103375
  14. Cell Physiol Biochem. 2022 Dec 12. 56(6): 692-706
    The Role of Exercise-Induced Reactive Oxygen Species (ROS) Hormesis in Aging: Friend or Foe.
    Ronny Lesmana, Cynthia Parameswari, Gabriela Fernanda Mandagi, Julianne Fay Wahyudi, Noah Jefferson Permana, Putri Teesa Radhiyanti, Julia Windi Gunadi.
      Reactive oxygen species (ROS) are oxygen derivatives that arise intrinsically from the oxidative phosphorylation process and extrinsically as a response to xenobiotics and pollution. ROS is involved in various conditions such as exercise, aging, inflammation, and neurodegenerative diseases. In the aging process, increased cellular senescence and decreased endogenous antioxidants also occur. Meanwhile, physical activity, specifically exercise, can modulate ROS. The impact of exercise on ROS varies from harmful to beneficial and depends on the type of exercise as they induce different types of ROS. Long-term exercise regulates signaling pathways that enhance antioxidant defense systems and control ROS production. This review will discuss studies on how exercise can regulate ROS and which type of exercise has a role in delaying the aging process. This review also exposes the impact of nutraceutical antioxidant agents that likely enhance the benefit of exercise. The nutraceutical antioxidants agents that likely enhance the benefit of exercise are creatine, whey, and ascorbic acid. Exercise is rewarding for the aging population concerning increasing their quality of life. Special consideration to exercise needs to be given to the type of exercise, and the exercise must be done continuously.
    Keywords:  Aging; Antioxidant; Exercise; Oxidative stress; ROS
    DOI:  https://doi.org/10.33594/000000594
  15. Ageing Res Rev. 2022 Dec 11. pii: S1568-1637(22)00260-4. [Epub ahead of print]84 101818
    Immunosenescence and inflamm-ageing in COVID-19.
    Mohammad Reza Zinatizadeh, Peyman Kheirandish Zarandi, Mohsen Ghiasi, Hamid Kooshki, Mozafar Mohammadi, Jafar Amani, Nima Rezaei.
      The destructive effects of coronavirus disease 2019 (COVID-19) on the elderly and people with cardiovascular disease have been proven. New findings shed light on the role of aging pathways on life span and health age. New therapies that focus on aging-related pathways may positively impact the treatment of this acute respiratory infection. Using new therapies that boost the level of the immune system can support the elderly with co-morbidities against the acute form of COVID-19. This article discusses the effect of the aging immune system against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the pathways affecting this severity of infection.
    Keywords:  COVID-19; Immunosenescence; Inflamm-ageing; SARS-CoV-2
    DOI:  https://doi.org/10.1016/j.arr.2022.101818
  16. Open Heart. 2022 Dec;pii: e002171. [Epub ahead of print]9(2):
    Nutraceutical activation of Sirt1: a review.
    James J DiNicolantonio, Mark F McCarty, James H O'Keefe.
      The deacetylase sirtuin 1 (Sirt1), activated by calorie restriction and fasting, exerts several complementary effects on cellular function that are favourable to healthspan; it is often thought of as an 'anti-aging' enzyme. Practical measures which might boost Sirt1 activity are therefore of considerable interest. A number of nutraceuticals have potential in this regard. Nutraceuticals reported to enhance Sirt1 synthesis or protein expression include ferulic acid, tetrahydrocurcumin, urolithin A, melatonin, astaxanthin, carnosic acid and neochlorogenic acid. The half-life of Sirt1 protein can be enhanced with the natural nicotinamide catabolite N1-methylnicotinamide. The availability of Sirt1's obligate substrate NAD+ can be increased in several ways: nicotinamide riboside and nicotinamide mononucleotide can function as substrates for NAD+ synthesis; activators of AMP-activated kinase-such as berberine-can increase expression of nicotinamide phosphoribosyltransferase, which is rate limiting for NAD+ synthesis; and nutraceutical quinones such as thymoquinone and pyrroloquinoline quinone can boost NAD+ by promoting oxidation of NADH. Induced ketosis-as via ingestion of medium-chain triglycerides-can increase NAD+ in the brain by lessening the reduction of NAD+ mediated by glycolysis. Post-translational modifications of Sirt1 by O-GlcNAcylation or sulfonation can increase its activity, suggesting that administration of glucosamine or of agents promoting hydrogen sulfide synthesis may aid Sirt1 activity. Although resveratrol has poor pharmacokinetics, it can bind to Sirt1 and activate it allosterically-as can so-called sirtuin-activating compound drugs. Since oxidative stress can reduce Sirt1 activity in multiple ways, effective antioxidant supplementation that blunts such stress may also help preserve Sirt1 activity in some circumstances. Combination nutraceutical regimens providing physiologically meaningful doses of several of these agents, capable of activating Sirt1 in complementary ways, may have considerable potential for health promotion. Such measures may also amplify the benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors in non-diabetic disorders, as these benefits appear to reflect upregulation of Sirt1 and AMP-activated protein kinase activities.
    Keywords:  atrial fibrillation; carotid artery diseases; peripheral vascular diseases
    DOI:  https://doi.org/10.1136/openhrt-2022-002171
  17. Arch Gerontol Geriatr. 2022 Dec 05. pii: S0167-4943(22)00284-9. [Epub ahead of print]106 104897
    Prefrailty subtypes differentially predict 5-year mortality in the functionally independent geriatric population.
    Yu-Shan Lee, Yi-Ming Chen, Yin-Yi Chou, Chu-Sheng Lin, Jun-Peng Chen, Fu-Hsuan Kuo, Cheng-Fu Lin, Shih-Yi Lin.
       INTRODUCTION: Both frailty and prefrailty (PF) are related to mortality. However, there is no consensus about the PF subtypes for prediction of the mortality risk. We aimed to compare the 5-year mortality of functionally independent geriatric outpatients with nonfrailty, different PF subtypes and frailty.
    METHODS: This was a single-center, retrospective cohort study. Community-dwelling older adults who visited the geriatric outpatient clinic in a healthcare institution in Taiwan were enrolled. PF1 was defined based on exhaustion and/or body weight loss whereas PF2 was defined by one or two of the following criteria: weakness, slowness, and low physical activity. Frailty was defined by three or more above criteria. Demographics and results of comprehensive geriatric assessment were compared and Kaplan-Meier survival analysis was used to determine the 5-year survival among the nonfrail, PF1, PF2 and frail groups.
    RESULTS: Of the 982 participants, the proportion of PF and frailty was high (PF 45.7% and frailty 24.5%). The cumulative 5-year survival rate of the nonfrail group, PF1, PF2 subgroups and frail group was 98.6%, 95.8%, 89.1% and 81.3% respectively. Age, male sex, PF2 subtype and frailty were significantly associated with 5-year mortality [hazard ratio (95% confidence interval) 1.05 (1.01-1.08), 1.96 (1.08-3.57), 5.18 (1.57-17.09), and 6.87 (2.05-23.04), respectively].
    DISCUSSION AND CONCLUSION: The proportion of PF and frailty was high in old outpatient population with functional independence. PF2 subtypes and frailty could influence the 5-year mortality risk in these participants. Identifying PF2 participants earlier and instituting prompt intervention may be beneficial in older patients.
    Keywords:  Functional independence; Mortality; Older people; Phenotype; Prefrailty
    DOI:  https://doi.org/10.1016/j.archger.2022.104897
  18. Nat Immunol. 2022 Dec 12.
    Aging-associated HELIOS deficiency in naive CD4+ T cells alters chromatin remodeling and promotes effector cell responses.
    Huimin Zhang, Rohit R Jadhav, Wenqiang Cao, Isabel N Goronzy, Tuantuan V Zhao, Jun Jin, Shozo Ohtsuki, Zhaolan Hu, Jose Morales, William J Greenleaf, Cornelia M Weyand, Jörg J Goronzy.
      Immune aging combines cellular defects in adaptive immunity with the activation of pathways causing a low-inflammatory state. Here we examined the influence of age on the kinetic changes in the epigenomic and transcriptional landscape induced by T cell receptor (TCR) stimulation in naive CD4+ T cells. Despite attenuated TCR signaling in older adults, TCR activation accelerated remodeling of the epigenome and induced transcription factor networks favoring effector cell differentiation. We identified increased phosphorylation of STAT5, at least in part due to aberrant IL-2 receptor and lower HELIOS expression, as upstream regulators. Human HELIOS-deficient, naive CD4+ T cells, when transferred into human-synovium-mouse chimeras, infiltrated tissues more efficiently. Inhibition of IL-2 or STAT5 activity in T cell responses of older adults restored the epigenetic response pattern to the one seen in young adults. In summary, reduced HELIOS expression in non-regulatory naive CD4+ T cells in older adults directs T cell fate decisions toward inflammatory effector cells that infiltrate tissue.
    DOI:  https://doi.org/10.1038/s41590-022-01369-x
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