bims-minfam 2022-08-21 papers

bims-minfam

Biomed News

on Inflammation and metabolism in ageing and cancer

Issue of 2022–08–21
twelve papers selected by
Ayesh Seneviratne, Western University

Metabolic changes in aging humans: current evidence and therapeutic strategies.
Inflammatory and immune markers in HIV-infected older adults on long-term antiretroviral therapy: Persistent elevation of sCD14 and of proinflammatory effector memory T cells.
Supplementing Glycine and N-Acetylcysteine (GlyNAC) in Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, and Aging Hallmarks: A Randomized Clinical Trial.
Association of extracellular vesicle inflammatory proteins and mortality.
Frailty: understanding the difference between age and ageing.
Aging of mesenchymal stem cell: machinery, markers, and strategies of fighting.
Characteristic Hallmarks of Aging and the Impact on Carcinogenesis.
Immunosenescence, aging and successful aging.
[Clonal hematopoiesis: causes and clinical implications].
Lipid metabolism in ferroptosis and ferroptosis-based cancer therapy.
HIV accelerates clonal hematopoiesis and cardiovascular aging.
Changes in the Severity of Frailty Among Older Adults After 12 Months of Supervised Home-Based Physical Exercise: A Randomized Clinical Trial.

J Clin Invest. 2022 Aug 15. pii: e158451. [Epub ahead of print]132(16):

Metabolic changes in aging humans: current evidence and therapeutic strategies.

Allyson K Palmer, Michael D Jensen.

Aging and metabolism are inextricably linked, and many age-related changes in body composition, including increased central adiposity and sarcopenia, have underpinnings in fundamental aging processes. These age-related changes are further exacerbated by a sedentary lifestyle and can be in part prevented by maintenance of activity with aging. Here we explore the age-related changes seen in individual metabolic tissues - adipose, muscle, and liver - as well as globally in older adults. We also discuss the available evidence for therapeutic interventions such as caloric restriction, resistance training, and senolytic and senomorphic drugs to maintain healthy metabolism with aging, focusing on data from human studies.

DOI: https://doi.org/10.1172/JCI158451
Aging Cell. 2022 Aug 16. e13681

Inflammatory and immune markers in HIV-infected older adults on long-term antiretroviral therapy: Persistent elevation of sCD14 and of proinflammatory effector memory T cells.

Makiko Watanabe, Mladen Jergovic, Lisa Davidson, Bonnie J LaFleur, Yvonne Castaneda, Carmine Martinez, Megan J Smithey, Raymond P Stowe, Elias K Haddad, Janko Nikolich-Žugich.

  HIV-positive patients whose viral loads are successfully controlled by active antiretroviral therapy (ART) show no clinical signs of AIDS. However, their lifespan is shorter compared with individuals with no HIV infection and they prematurely exhibit a multitude of chronic diseases typically associated with advanced age. It was hypothesized that immune system aging may correlate with, and provide useful biomarkers for, this premature loss of healthspan in HIV-positive subjects. Here, we tested whether the immune correlates of aging, including cell numbers and phenotypes, inflammatory status, and control of human cytomegalovirus (hCMV) in HIV-positive subjects on long-term successful ART (HIV+) may reveal increased "immunological age" compared with HIV-negative, age-matched cohort (HIV-) in participants between 50 and 69 years of age. Specifically, we expected that younger HIV+ subjects may immunologically resemble older individuals without HIV. We found no evidence to support this hypothesis. While T cells from HIV+ participants displayed differential expression in several differentiation and/or inhibitory/exhaustion markers in different T cell subpopulations, aging by a decade did not pronounce these changes. Similarly, while the HIV+ participants exhibited higher T cell responses and elevated inflammatory marker levels in plasma, indicative of chronic inflammation, this trait was not age-sensitive. We did find differences in immune control of hCMV, and, more importantly, a sustained elevation of sCD14 and of proinflammatory CD4 and CD8 T cell responses across age groups, pointing towards uncontrolled inflammation as a factor in reduced healthspan in successfully treated older HIV+ patients.

Keywords:  HIV; antiretroviral therapy; immune aging; sCD14

DOI:  https://doi.org/10.1111/acel.13681
J Gerontol A Biol Sci Med Sci. 2022 Aug 17. pii: glac135. [Epub ahead of print]

Supplementing Glycine and N-Acetylcysteine (GlyNAC) in Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, and Aging Hallmarks: A Randomized Clinical Trial.

Premranjan Kumar, Chun Liu, James Suliburk, Jean W Hsu, Raja Muthupillai, Farook Jahoor, Charles G Minard, George E Taffet, Rajagopal V Sekhar.

   BACKGROUND: Elevated oxidative stress (OxS), mitochondrial dysfunction, and hallmarks of aging are identified as key contributors to aging, but improving/reversing these defects in older adults (OA) is challenging. In prior studies, we identified that deficiency of the intracellular antioxidant glutathione (GSH) could play a role and reported that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improved GSH deficiency, OxS, mitochondrial fatty-acid oxidation (MFO), and insulin resistance (IR). To test whether GlyNAC supplementation in OA could improve GSH deficiency, OxS, mitochondrial dysfunction, IR, physical function, and aging hallmarks, we conducted a placebo-controlled randomized clinical trial.
METHODS: Twenty-four OA and 12 young adults (YA) were studied. OA was randomized to receive either GlyNAC (N = 12) or isonitrogenous alanine placebo (N = 12) for 16-weeks; YA (N = 12) received GlyNAC for 2-weeks. Participants were studied before, after 2-weeks, and after 16-weeks of supplementation to assess GSH concentrations, OxS, MFO, molecular regulators of energy metabolism, inflammation, endothelial function, IR, aging hallmarks, gait speed, muscle strength, 6-minute walk test, body composition, and blood pressure.
RESULTS: Compared to YA, OA had GSH deficiency, OxS, mitochondrial dysfunction (with defective molecular regulation), inflammation, endothelial dysfunction, IR, multiple aging hallmarks, impaired physical function, increased waist circumference, and systolic blood pressure. GlyNAC (and not placebo) supplementation in OA improved/corrected these defects.
CONCLUSION: GlyNAC supplementation in OA for 16-weeks was safe and well-tolerated. By combining the benefits of glycine, NAC and GSH, GlyNAC is an effective nutritional supplement that improves and reverses multiple age-associated abnormalities to promote health in aging humans. Clinical Trials Registration Number: NCT01870193.

Keywords:  Clinical trials; GlyNAC; Metabolism; Oxidative stress; Successful aging

DOI:  https://doi.org/10.1093/gerona/glac135
Sci Rep. 2022 Aug 18. 12(1): 14049

Association of extracellular vesicle inflammatory proteins and mortality.

Nicole Noren Hooten, Stephanie Torres, Nicolle A Mode, Alan B Zonderman, Paritosh Ghosh, Ngozi Ezike, Michele K Evans.

Even before the COVID-19 pandemic declines in life expectancy in the United States were attributed to increased mortality rates in midlife adults across racial and ethnic groups, indicating a need for markers to identify individuals at risk for early mortality. Extracellular vesicles (EVs) are small, lipid-bound vesicles capable of shuttling functional proteins, nucleic acids, and lipids. Given their role as intercellular communicators and potential biomarkers of disease, we explored whether circulating EVs may be markers of mortality in a prospective, racially, and socioeconomically diverse middle-aged cohort. We isolated plasma EVs from 76 individuals (mean age = 59.6 years) who died within a 5 year period and 76 surviving individuals matched by age, race, and poverty status. There were no significant differences in EV concentration, size, or EV-associated mitochondrial DNA levels associated with mortality. We found that several EV-associated inflammatory proteins including CCL23, CSF-1, CXCL9, GDNF, MCP-1, STAMBP, and 4E-BP1 were significantly associated with mortality. IL-10RB and CDCP1 were more likely to be present in plasma EVs from deceased individuals than in their alive counterparts. We also report differences in EV-associated inflammatory proteins with poverty status, race, and sex. Our results suggest that plasma EV-associated inflammatory proteins are promising potential clinical biomarkers of mortality.

DOI: https://doi.org/10.1038/s41598-022-17944-z
Age Ageing. 2022 Aug 02. pii: afac185. [Epub ahead of print]51(8):

Frailty: understanding the difference between age and ageing.

Emily H Gordon, Ruth E Hubbard.

  In the past, illness and dependence were viewed as inevitable consequences of old age. Now, we understand that there is a difference between age (the passing of chronological time) and ageing (the increased risk of adverse outcomes over time). Over the last 50 years, 'frailty' research has established that ageing is heterogeneous, variable and malleable. Significant advances have been made in frailty measurement (description of clinical features and development of clinical models), mechanisms (insights into pathogenesis) and management (development of interventions to reduce and/or prevent progression). Subsequently, the concept of frailty has informed health policy and clinical practice and started to change perceptions of older age held by the general public and the health sector. Here, we overview key achievements in frailty research and clinical practice and highlight the considerable number of known unknowns that may be addressed in the future.

Keywords:  ageing; frailty; management; measurement; mechanisms; older people

DOI:  https://doi.org/10.1093/ageing/afac185
Cell Mol Biol Lett. 2022 Aug 19. 27(1): 69

Aging of mesenchymal stem cell: machinery, markers, and strategies of fighting.

Mahmoud Al-Azab, Mohammed Safi, Elina Idiiatullina, Fadhl Al-Shaebi, Mohamed Y Zaky.

  Human mesenchymal stem cells (MSCs) are primary multipotent cells capable of differentiating into osteocytes, chondrocytes, and adipocytes when stimulated under appropriate conditions. The role of MSCs in tissue homeostasis, aging-related diseases, and cellular therapy is clinically suggested. As aging is a universal problem that has large socioeconomic effects, an improved understanding of the concepts of aging can direct public policies that reduce its adverse impacts on the healthcare system and humanity. Several studies of aging have been carried out over several years to understand the phenomenon and different factors affecting human aging. A reduced ability of adult stem cell populations to reproduce and regenerate is one of the main contributors to the human aging process. In this context, MSCs senescence is a major challenge in front of cellular therapy advancement. Many factors, ranging from genetic and metabolic pathways to extrinsic factors through various cellular signaling pathways, are involved in regulating the mechanism of MSC senescence. To better understand and reverse cellular senescence, this review highlights the underlying mechanisms and signs of MSC cellular senescence, and discusses the strategies to combat aging and cellular senescence.

Keywords:  Aging; Cellular senescence; Differentiation; Mesenchymal stem cell; Senescence markers; Anti-cellular senescence

DOI:  https://doi.org/10.1186/s11658-022-00366-0
Curr Cancer Drug Targets. 2022 Aug 16.

Characteristic Hallmarks of Aging and the Impact on Carcinogenesis.

Sergio Terracina, Giampiero Ferraguti, Carla Petrella, Sabina Maria Bruno, Giovanna Blaconà, Maria Grazia Di Certo, Antonio Minni, Antonio Greco, Angela Musacchio, Massimo Ralli, Luigi Tarani, Mauro Ceccanti, Antonella Polimeni, Viviana Triaca, Marco Fiore.

  Evidence shows that there is a synergistic, bidirectional association between cancer and aging with many shared traits. Age itself is a risk factor for the onset of most cancers while evidence suggests that cancer and its treatments might accelerate aging by causing genotoxic and cytotoxic insults. Aging has been associated with a series of alterations that can be linked to cancer: i) genomic instability caused by DNA damage or epigenetic alterations coupled with repair errors, which lead to progressive accumulation of mutations; ii) telomere attrition with possible impairment of telomerase, shelterin complex, or the trimeric complex (Cdc13, Stn1 and Ten1 - CST) activities associated with abnormalities in DNA replication and repair; iii) altered proteostasis especially when leading to an augmented proteasome, chaperon and autophagy-lysosome activity; iv) mitochondrial dysfunction causing oxidative stress; v) cellular senescence; vi) stem cells exhaustion, intercellular altered communication and deregulated nutrient sensing which are associated with microenvironmental modifications which may facilitate the subsequential role of cancer stem cells. Nowadays anti-growth factor agents and epigenetic therapies seem to assume an increasing role to fight aging-related diseases, especially cancer. This report aims to discuss the impact of age on cancer growth.

Keywords:  aging; cancer; epigenetic; genomic instability; microenvironment; oxidative stress.

DOI:  https://doi.org/10.2174/1568009622666220816120353
Front Immunol. 2022 ;13 942796

Immunosenescence, aging and successful aging.

Yunan Wang, Chen Dong, Yudian Han, Zhifeng Gu, Chi Sun.

  Aging induces a series of immune related changes, which is called immunosenescence, playing important roles in many age-related diseases, especially neurodegenerative diseases, tumors, cardiovascular diseases, autoimmune diseases and coronavirus disease 2019(COVID-19). However, the mechanism of immunosenescence, the association with aging and successful aging, and the effects on diseases are not revealed obviously. In order to provide theoretical basis for preventing or controlling diseases effectively and achieve successful aging, we conducted the review and found that changes of aging-related phenotypes, deterioration of immune organ function and alterations of immune cell subsets participated in the process of immunosenescence, which had great effects on the occurrence and development of age-related diseases.

Keywords:  age-related diseases; centenarian; immunosenescence; inflammation; successful aging

DOI:  https://doi.org/10.3389/fimmu.2022.942796
Inn Med (Heidelb). 2022 Aug 15.

[Clonal hematopoiesis: causes and clinical implications].

Andreas Burchert.

  Clonal hematopoiesis of indeterminate potential (CHIP) refers to hematopoiesis from stem cells with mutations in leukemia-associated driver genes. These confer increased stress tolerance and expansive potential to stem cell clones. Patients with CHIP are hematologically healthy. The main risk factor for the development of CHIP is age or chronic inflammatory processes associated with aging, so-called "inflammaging". Therefore, the correlation of age-associated comorbidities with the detection of CHIP is not coincidental. CHIP is associated with, among other things, a significantly increased risk of cardiovascular disease and increased all-cause mortality. From a pathomechanistic perspective, CHIP leads to increased secretion of proinflammatory cytokines. It is also associated with a significantly increased risk of developing hematologic neoplasms. Thus, the treatment of CHIP could suppress the occurrence of hematologic neoplasms and prevent age-associated diseases.

Keywords:  Cardiovascular comorbidity; Clonal hematopoiesis of indeterminate potential; Hematologic neoplasms; Inflammaging; Variant allele frequency

DOI:  https://doi.org/10.1007/s00108-022-01388-8
Front Oncol. 2022 ;12 941618

Lipid metabolism in ferroptosis and ferroptosis-based cancer therapy.

Yonghao Sun, Zuoxing Xue, Tao Huang, Xiangyu Che, Guangzhen Wu.

  Ferroptosis refers to iron-dependent, specialized, and regulated-necrosis mediated by lipid peroxidation, which is closely related to a variety of diseases, including cancer. Tumor cells undergo extensive changes in lipid metabolism, including lipid peroxidation and ferroptosis. Changes in lipid metabolism are critical for the regulation of ferroptosis and thus have important roles in cancer therapy. In this review, we introduce the characteristics of ferroptosis and briefly analyze the links between several metabolic mechanisms and ferroptosis. The effects of lipid peroxides, several signaling pathways, and the molecules and pathways involved in lipid metabolism on ferroptosis were extensively analyzed. Finally, our review highlights some ferroptosis-based treatments and presents some methods and examples of how these treatments can be combined with other treatments.

Keywords:  ferroptosis; lipid metabolism; lipid peroxidation; tumor; tumor therapy

DOI:  https://doi.org/10.3389/fonc.2022.941618
AIDS. 2022 Sep 01. 36(11): 1599-1601

HIV accelerates clonal hematopoiesis and cardiovascular aging.

Tetsuo Tsukamoto.

DOI: https://doi.org/10.1097/QAD.0000000000003330
J Am Med Dir Assoc. 2022 Aug 16. pii: S1525-8610(22)00551-5. [Epub ahead of print]

Changes in the Severity of Frailty Among Older Adults After 12 Months of Supervised Home-Based Physical Exercise: A Randomized Clinical Trial.

Sara Suikkanen, Paula Soukkio, Hannu Kautiainen, Sanna Kääriä, Markku T Hupli, Sarianna Sipilä, Kaisu Pitkälä, Eeva Aartolahti, Katriina Kukkonen-Harjula.

   OBJECTIVE: To investigate the effects of 12 months of physiotherapist-supervised, home-based physical exercise on the severity of frailty and on the prevalence of the 5 frailty phenotype criteria, using secondary analyses.
DESIGN: Randomized clinical trial, with 1:1 allocation into 12-month home-based physical exercise, or usual care. The multicomponent exercise sessions (60 minutes) were supervised by the physiotherapist and included strength, balance, functional, and flexibility exercises twice a week at participants' homes.
SETTING AND PARTICIPANTS: Home-dwelling older adults aged ≥65 years who were frail (meeting 3-5 criteria) or prefrail (1-2 criteria) according to frailty phenotype criteria.
METHODS: The severity of frailty (nonfrail, prefrail, or frail) was assessed using frailty phenotype criteria, and the prevalence of each frailty criterion (weight loss, low physical activity, exhaustion, weakness, and slowness) were assessed at baseline and at 12 months.
RESULTS: Two hundred ninety-nine persons were included in the analyses, of whom 184 were prefrail and 115 were frail at baseline. Their mean age was 82.5 (SD 6.3) years, and 75% were women. There was a significant difference between the exercise and usual care groups' transitions to different frailty states from baseline to 12 months among those who at baseline were prefrail (P = .032) and frail (P = .009). At 12 months, the mean number of frailty criteria had decreased in the exercise group (-0.27, 95% CI -0.47, -0.08) and remained unchanged in the usual care group (0.01, 95% CI -0.16, 0.18; P = .042). The prevalence of the exhaustion (P = .009) and the low physical activity (P < .001) criteria were lower at 12 months in the exercise group than in the usual care group.
CONCLUSIONS AND IMPLICATIONS: The severity of frailty can be reduced through 12-month supervised home-based exercise training. Exercise should be included in the care of older adults with signs of frailty.

Keywords:  Frailty; older adults; physical exercise; rehabilitation

DOI:  https://doi.org/10.1016/j.jamda.2022.07.010