bims-longev Biomed News
on Longevity
Issue of 2023–04–16
fourteen papers selected by
Andreea Nitescu
  1. Cancer prevention with rapamycin.
  2. Cycloastragenol: A Novel Senolytic Agent That Induces Senescent Cell Apoptosis and Restores Physical Function in TBI-Aged Mice.
  3. Rapamycin restores peripheral blood flow in aged mice and in mouse models of atherosclerosis and Alzheimer's disease.
  4. Ketogenic Diet as a Promising Non-Drug Intervention for Alzheimer's Disease: Mechanisms and Clinical Implications.
  5. Nutrition and cognitive health: A life course approach.
  6. Proteostasis and lysosomal quality control deficits in Alzheimer's disease neurons.
  7. Ketone bodies: A double-edged sword for mammalian life span.
  8. The relationship between epigenetic age and the hallmarks of aging in human cells.
  9. Canonical and extra-telomeric functions of telomerase: Implications for healthy ageing conferred by endurance training.
  10. Geroprotective Effect of Levilactobacillus brevis and Weizmannia coagulans in Caenorhabditis elegans.
  11. Ferroptosis Regulated by Hypoxia in Cells.
  12. The Potential Benefits of Quercetin for Brain Health: A Review of Anti-Inflammatory and Neuroprotective Mechanisms.
  13. Income raises human well-being indefinitely, but age consistently slashes it.
  14. Urolithin A Produced by Novel Microbial Fermentation Possesses Anti-aging Effects by Improving Mitophagy and Reducing Reactive Oxygen Species in Caenorhabditis elegans.
  1. Oncotarget. 2023 Apr 14. 14 342-350
    Cancer prevention with rapamycin.
    Mikhail V Blagosklonny.
      Rapamycin (sirolimus) and other rapalogs (everolimus) are anti-cancer and anti-aging drugs, which delay cancer by directly targeting pre-cancerous cells and, indirectly, by slowing down organism aging. Cancer is an age-related disease and, figuratively, by slowing down time (and aging), rapamycin may delay cancer. In several dozen murine models, rapamycin robustly and reproducibly prevents cancer. Rapamycin slows cell proliferation and tumor progression, thus delaying the onset of cancer in carcinogen-treated, genetically cancer-prone and normal mice. Data on the use of rapamycin and everolimus in organ-transplant patients are consistent with their cancer-preventive effects. Treatment with rapamycin was proposed to prevent lung cancer in smokers and former smokers. Clinical trials in high-risk populations are warranted.
    Keywords:  aging; cancer; chemoprevention; lung; rapamycin
    DOI:  https://doi.org/10.18632/oncotarget.28410
  2. Int J Mol Sci. 2023 Mar 31. pii: 6554. [Epub ahead of print]24(7):
    Cycloastragenol: A Novel Senolytic Agent That Induces Senescent Cell Apoptosis and Restores Physical Function in TBI-Aged Mice.
    Yanghuan Zhang, Dongxiao Gao, Yang Yuan, Runzi Zheng, Manting Sun, Shuting Jia, Jing Liu.
      Accumulating evidence indicates that the increased burden of senescent cells (SCs) in aged organisms plays an important role in many age-associated diseases. The pharmacological elimination of SCs with "senolytics" has been emerging as a new therapy for age-related diseases and extending the healthy lifespan. In the present study, we identified that cycloastragenol (CAG), a secondary metabolite isolated from Astragalus membrananceus, delays age-related symptoms in mice through its senolytic activity against SCs. By screening a series of compounds, we found that CAG selectively kills SCs by inducing SCs apoptosis and that this process is associated with the inhibition of Bcl-2 antiapoptotic family proteins and the PI3K/AKT/mTOR pathway. In addition, CAG treatment also suppressed the development of the senescence-associated secretory phenotype (SASP) in SCs, thereby inhibiting cell migration mediated by the SASP. Furthermore, the administration of CAG for 2 weeks to mice with irradiation-induced aging alleviated the burden of SCs and improved the animals' age-related physical dysfunction. Overall, our studies demonstrate that CAG is a novel senolytic agent with in vivo activity that has the potential to be used in the treatment of age-related diseases.
    Keywords:  CAG; aging; cell senescence; senolytic
    DOI:  https://doi.org/10.3390/ijms24076554
  3. Geroscience. 2023 Apr 13.
    Rapamycin restores peripheral blood flow in aged mice and in mouse models of atherosclerosis and Alzheimer's disease.
    Candice E Van Skike, Nicholas DeRosa, Veronica Galvan, Stacy A Hussong.
      Peripheral artery disease (PAD), defined as reduced blood flow to the lower limbs, is a serious disorder that can lead to loss of function in the lower extremities and even loss of limbs. One of the main risk factors for PAD is age, with up to 25% of adults over the age of 55 and up to 40% over the age of 80 presenting with some form of the disease. While age is the largest risk factor for PAD, other risk factors include atherosclerosis, smoking, hypertension, and diabetes. Furthermore, previous studies have suggested that the incidence of PAD is significantly increased in patients with Alzheimer's disease (AD). Attenuation of mTOR with rapamycin significantly improves cerebral blood flow and heart function in aged rodents as well as in mouse models of atherosclerosis, atherosclerosis-driven cognitive impairment, and AD. In this study, we show that rapamycin treatment improves peripheral blood flow in aged mice and in mouse models of atherosclerosis and AD. Inhibition of mTOR with rapamycin ameliorates deficits in baseline hind paw perfusion in aged mice and restores levels of blood flow to levels indistinguishable from those of young controls. Furthermore, rapamycin treatment ameliorates peripheral blood flow deficits in mouse models of atherosclerosis and AD. These data indicate that mTOR is causally involved in the reduction of blood flow to lower limbs associated with aging, atherosclerosis, and AD-like progression in model mice. Rapamycin or other mTOR inhibitors may have potential as interventions to treat peripheral artery disease and other peripheral circulation-related conditions.
    Keywords:  Aging; Alzheimer’s disease; Atherosclerosis; Peripheral blood flow; Rapamycin; mTOR
    DOI:  https://doi.org/10.1007/s11357-023-00786-6
  4. J Alzheimers Dis. 2023 Mar 04.
    Ketogenic Diet as a Promising Non-Drug Intervention for Alzheimer's Disease: Mechanisms and Clinical Implications.
    Yunlong Xu, Fuxiang Zheng, Qi Zhong, Yingjie Zhu.
      Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is mainly characterized by cognitive deficits. Although many studies have been devoted to developing disease-modifying therapies, there has been no effective therapy until now. However, dietary interventions may be a potential strategy to treat AD. The ketogenic diet (KD) is a high-fat and low-carbohydrate diet with adequate protein. KD increases the levels of ketone bodies, providing an alternative energy source when there is not sufficient energy supply because of impaired glucose metabolism. Accumulating preclinical and clinical studies have shown that a KD is beneficial to AD. The potential underlying mechanisms include improved mitochondrial function, optimization of gut microbiota composition, and reduced neuroinflammation and oxidative stress. The review provides an update on clinical and preclinical research on the effects of KD or medium-chain triglyceride supplementation on symptoms and pathophysiology in AD. We also detail the potential mechanisms of KD, involving amyloid and tau proteins, neuroinflammation, gut microbiota, oxidative stress, and brain metabolism. We aimed to determine the function of the KD in AD and outline important aspects of the mechanism, providing a reference for the implementation of the KD as a potential therapeutic strategy for AD.
    Keywords:  Alzheimer’s disease; amyloid; dementia; ketogenic diet; ketone bodies therapy; ketone body; neuroinflammation; tau protein
    DOI:  https://doi.org/10.3233/JAD-230002
  5. Front Public Health. 2023 ;11 1023907
    Nutrition and cognitive health: A life course approach.
    Seema Puri, Majida Shaheen, Bhanvi Grover.
      Multiple factors affect cognitive health, such as age-related changes in the brain, injuries, mood disorders, substance abuse, and diseases. While some cannot be changed, evidence exists of many potentially possibly modifiable lifestyle factors: diet, physical activity, cognitive and social engagement, smoking and alcohol consumption which may stabilize or improve declining cognitive function. In nutrition, the focus has been mainly on its role in brain development in the early years. There is a strong emerging need to identify the role of diet and nutrition factors on age-related cognitive decline, which will open up the use of new approaches for prevention, treatment or management of age-related disorders and maintaining a good quality of life among older adults. While data on effect of high protein diets is not consistent, low-fat diets are protective against cognitive decline. Several micronutrients like B group vitamins and iron, as well as many polyphenols play a crucial role in cognitive health. Mediterranean, Nordic, DASH, and MIND diets are linked to a lower risk of cognitive decline and dementia. The relationship between the gut microbiome and brain function through the gut-brain axis has led to the emergence of data on the beneficial effects of dietary fibers and probiotics through the management of gut microbes. A "whole diet" approach as well as macro- and micro-nutrient intake levels that have protective effects against cardiovascular diseases are most likely to be effective against neurodegenerative disorders too. Young adulthood and middle age are crucial periods for determining cognitive health in old age. The importance of cardio metabolic risk factors such as obesity and hypertension, smoking and physical inactivity that develop in middle age suggest that preventive approaches are required for target populations in their 40s and 50s, much before they develop dementia. The commonality of dementia risk with cardiovascular and diabetes risk suggests that dementia could be added to present non-communicable disease management programs in primary healthcare and broader public health programs.
    Keywords:  cognitive health; dementia; diet; healthy aging; life course approach; nutrient
    DOI:  https://doi.org/10.3389/fpubh.2023.1023907
  6. bioRxiv. 2023 Mar 27. pii: 2023.03.27.534444. [Epub ahead of print]
    Proteostasis and lysosomal quality control deficits in Alzheimer's disease neurons.
    Ching-Chieh Chou, Ryan Vest, Miguel A Prado, Joshua Wilson-Grady, Joao A Paulo, Yohei Shibuya, Patricia Moran-Losada, Ting-Ting Lee, Jian Luo, Steven P Gygi, Jeffery W Kelly, Daniel Finley, Marius Wernig, Tony Wyss-Coray, Judith Frydman.
      The role of proteostasis and organelle homeostasis dysfunction in human aging and Alzheimer's disease (AD) remains unclear. Analyzing proteome-wide changes in human donor fibroblasts and their corresponding transdifferentiated neurons (tNeurons), we find aging and AD synergistically impair multiple proteostasis pathways, most notably lysosomal quality control (LQC). In particular, we show that ESCRT-mediated lysosomal repair defects are associated with both sporadic and PSEN1 familial AD. Aging- and AD-linked defects are detected in fibroblasts but highly exacerbated in tNeurons, leading to enhanced neuronal vulnerability, unrepaired lysosomal damage, inflammatory factor secretion and cytotoxicity. Surprisingly, tNeurons from aged and AD donors spontaneously develop amyloid-β inclusions co-localizing with LQC markers, LAMP1/2-positive lysosomes and proteostasis factors; we observe similar inclusions in brain tissue from AD patients and APP-transgenic mice. Importantly, compounds enhancing lysosomal function broadly ameliorate these AD-associated pathologies. Our findings establish cell-autonomous LQC dysfunction in neurons as a central vulnerability in aging and AD pathogenesis.
    DOI:  https://doi.org/10.1101/2023.03.27.534444
  7. Aging Cell. 2023 Apr 14. e13833
    Ketone bodies: A double-edged sword for mammalian life span.
    Issei Tomita, Hiroaki Tsuruta, Mako Yasuda-Yamahara, Kosuke Yamahara, Shogo Kuwagata, Yuki Tanaka-Sasaki, Masami Chin-Kanasaki, Yukihiro Fujita, Eiichiro Nishi, Hideki Katagiri, Hiroshi Maegawa, Shinji Kume.
      Accumulating evidence suggests health benefits of ketone bodies, and especially for longevity. However, the precise role of endogenous ketogenesis in mammalian life span, and the safety and efficacy of the long-term exogenous supplementation of ketone bodies remain unclear. In the present study, we show that a deficiency in endogenous ketogenesis, induced by whole-body Hmgcs2 deletion, shortens life span in mice, and that this is prevented by daily ketone body supplementation using a diet containing 1,3-butanediol, a precursor of β-hydroxybutyrate. Furthermore, feeding the 1,3-butanediol-containing diet from early in life increases midlife mortality in normal mice, but in aged mice it extends life span and prevents the high mortality associated with atherosclerosis in ApoE-deficient mice. By contrast, an ad libitum low-carbohydrate ketogenic diet markedly increases mortality. In conclusion, endogenous ketogenesis affects mammalian survival, and ketone body supplementation may represent a double-edged sword with respect to survival, depending on the method of administration and health status.
    Keywords:  Hmgcs2; ketone body; longevity; low-carbohydrate ketogenic diet
    DOI:  https://doi.org/10.1111/acel.13833
  8. Nat Aging. 2022 Jun;2(6): 484-493
    The relationship between epigenetic age and the hallmarks of aging in human cells.
    Sylwia Kabacik, Donna Lowe, Leonie Fransen, Martin Leonard, Siew-Lan Ang, Christopher Whiteman, Sarah Corsi, Howard Cohen, Sarah Felton, Radhika Bali, Steve Horvath, Ken Raj.
      Epigenetic clocks are mathematically derived age estimators that are based on combinations of methylation values that change with age at specific CpGs in the genome. These clocks are widely used to measure the age of tissues and cells1,2. The discrepancy between epigenetic age (EpiAge), as estimated by these clocks, and chronological age is referred to as EpiAge acceleration. Epidemiological studies have linked EpiAge acceleration to a wide variety of pathologies, health states, lifestyle, mental state and environmental factors2, indicating that epigenetic clocks tap into critical biological processes that are involved in aging. Despite the importance of this inference, the mechanisms underpinning these clocks remained largely uncharacterized and unelucidated. Here, using primary human cells, we set out to investigate whether epigenetic aging is the manifestation of one or more of the aging hallmarks previously identified3. We show that although epigenetic aging is distinct from cellular senescence, telomere attrition and genomic instability, it is associated with nutrient sensing, mitochondrial activity and stem cell composition.
    DOI:  https://doi.org/10.1038/s43587-022-00220-0
  9. Aging Cell. 2023 Apr 11. e13836
    Canonical and extra-telomeric functions of telomerase: Implications for healthy ageing conferred by endurance training.
    Joshua Denham.
      Telomerase preserves genomic integrity by maintaining and protecting the telomeres. Seminal findings from 1985 revealed the canonical role of telomerase and motivated investigations into potential therapeutic strategies to combat one of the hallmarks of ageing-telomere attrition. Since then, the field of telomere biology has rapidly expanded, with telomerase serving essential roles in cancer and cell development through its canonical function. However, telomerase also exerts critical extra-telomeric functions through its protein (telomerase reverse transcriptase, TERT) and RNA components (telomerase RNA component, TERC). Telomerase re-activation or ectopic expression promotes survival and permits unlimited proliferation in tumours and healthy non-malignant cells. TERT gene therapies improve health and lifespan in ageing mice and mouse models of age-related diseases. The extra-telomeric functions of telomerase are critical to ageing. These include protection against oxidative stress, orchestration of chromatin modifications and transcription, and regulation of angiogenesis and metabolism (e.g. mitochondrial function and glucose control). Given these biological functions are key adaptations to endurance training and the recent meta-analytical findings that indicate exercise up-regulates TERT and telomerase, a comprehensive discussion on the implications of the canonical and extra-telomeric roles of telomerase is warranted. This review highlights the therapeutic benefits of telomerase-based treatments for idiopathic and chronic diseases that are linked to ageing. Discussion on the canonical and extra-telomeric roles of telomerase are presented, followed by a detailed summary of the evidence on how exercise influences telomerase. Finally, the potential cell signalling underpinning the exercise-induced modulation of telomerase are discussed with directions for future research.
    Keywords:   TERT ; epigenetics; exercise; metabolism; oxidative stress; telomeres
    DOI:  https://doi.org/10.1111/acel.13836
  10. Probiotics Antimicrob Proteins. 2023 Apr 10.
    Geroprotective Effect of Levilactobacillus brevis and Weizmannia coagulans in Caenorhabditis elegans.
    Govindhan Thiruppathi, Amirthalingam Mohankumar, Duraisamy Kalaiselvi, Muthusamy Velumani, Periyakali Saravana Bhavan, Paramasivam Premasudha, Shinkichi Tawata, Palanisamy Sundararaj.
      The prophylactic use of lactic acid bacteria (LAB) to maintain human health is one of the most important research areas in recent times. LAB supplementation confers a wide range of health benefits to the host, but few studies have focused on their possible role in delaying the aging process. This study explored the health and life-promoting properties of two LAB, Levilactobacillus brevis and Weizmannia coagulans, using the Caenorhabditis elegans model. We found that L. brevis and W. coagulans enhanced the intestinal integrity and intestinal barrier functions without affecting the overall physiological functions of C. elegans. Wild-type worms preconditioned with LAB strains increased their survival under oxidative and thermal stress conditions by reducing intracellular reactive oxygen levels. Live L. brevis and W. coagulans significantly extended the lifespan of C. elegans under standard laboratory conditions independently of dietary restrictions. Genetic and reporter gene expression analysis revealed that L. brevis and W. coagulans extend lifespan via insulin/insulin-like growth factor-1 signaling and the p38 MAPK signaling axis. Furthermore, sirtuin, JNK MAPK, and mitochondrial respiratory complexes were found to be partially involved in W. coagulans-mediated lifespan extension and stress resilience. Preconditioning with LAB ameliorated age-related functional decline in C. elegans and reduced ectopic fat deposition in an NHR-49-dependent manner. Together, our findings indicated that L. brevis and W. coagulans are worth exploring further as "gerobiotic" candidates to delay aging and improve the healthspan of the host.
    Keywords:  Caenorhabditis elegans; Gerobiotics; Lactic acid bacteria; Levilactobacillus brevis; Longevity; Weizmannia coagulans
    DOI:  https://doi.org/10.1007/s12602-023-10060-y
  11. Cells. 2023 Mar 30. pii: 1050. [Epub ahead of print]12(7):
    Ferroptosis Regulated by Hypoxia in Cells.
    Xiangnan Zheng, Yuqiong Liang, Cen Zhang.
      Ferroptosis is an oxidative damage-related, iron-dependent regulated cell death with intracellular lipid peroxide accumulation, which is associated with many physiological and pathological processes. It exhibits unique features that are morphologically, biochemically, and immunologically distinct from other regulated cell death forms. Ferroptosis is regulated by iron metabolism, lipid metabolism, anti-oxidant defense systems, as well as various signal pathways. Hypoxia, which is found in a group of physiological and pathological conditions, can affect multiple cellular functions by activation of the hypoxia-inducible factor (HIF) signaling and other mechanisms. Emerging evidence demonstrated that hypoxia regulates ferroptosis in certain cell types and conditions. In this review, we summarize the basic mechanisms and regulations of ferroptosis and hypoxia, as well as the regulation of ferroptosis by hypoxia in physiological and pathological conditions, which may contribute to the numerous diseases therapies.
    Keywords:  ferroptosis; hypoxia; hypoxia-inducible factors; iron metabolism; lipid peroxidation
    DOI:  https://doi.org/10.3390/cells12071050
  12. Int J Mol Sci. 2023 Mar 28. pii: 6328. [Epub ahead of print]24(7):
    The Potential Benefits of Quercetin for Brain Health: A Review of Anti-Inflammatory and Neuroprotective Mechanisms.
    Ming-Chang Chiang, Tsung-Yu Tsai, Chieh-Ju Wang.
      Neuroinflammation is a critical factor in developing and progressing numerous brain diseases, including neurodegenerative diseases. Chronic or excessive neuroinflammation can lead to neurotoxicity, causing brain damage and contributing to the onset and progression of various brain diseases. Therefore, understanding neuroinflammation mechanisms and developing strategies to control them is crucial for treating brain diseases. Studies have shown that neuroinflammation plays a vital role in the progression of neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's (PD), and stroke. Additionally, the effects of PM2.5 pollution on the brain, including neuroinflammation and neurotoxicity, are well-documented. Quercetin is a flavonoid, a plant pigment in many fruits, vegetables, and grains. Quercetin has been studied for its potential health benefits, including its anti-inflammatory, antioxidant, and anti-cancer properties. Quercetin may also have a positive impact on immune function and allergy symptoms. In addition, quercetin has been shown to have anti-inflammatory and neuroprotective properties and can activate AMP-activated protein kinase (AMPK), a cellular energy sensor that modulates inflammation and oxidative stress. By reducing inflammation and protecting against neuroinflammatory toxicity, quercetin holds promise as a safe and effective adjunctive therapy for treating neurodegenerative diseases and other brain disorders. Understanding and controlling the mechanisms of NF-κB and NLRP3 inflammasome pathways are crucial for preventing and treating conditions, and quercetin may be a promising tool in this effort. This review article aims to discuss the role of neuroinflammation in the development and progression of various brain disorders, including neurodegenerative diseases and stroke, and the impact of PM2.5 pollution on the brain. The paper also highlights quercetin's potential health benefits and anti-inflammatory and neuroprotective properties.
    Keywords:  AMPK; NF-κB; NLRP3 inflammasome; anti-inflammatory agents; neuroprotection; quercetin
    DOI:  https://doi.org/10.3390/ijms24076328
  13. Sci Rep. 2023 Apr 11. 13(1): 5905
    Income raises human well-being indefinitely, but age consistently slashes it.
    Chao Li, Shunsuke Managi.
      The relationships among human well-being, income, and age have long been debated. The association between human well-being and income is believed to be U-shaped, although the reasons remain elusive. A recent study shows a turning point in the link between human well-being and income; that is, increased income does not always improve well-being. However, the mechanisms of the effects of income and age on human well-being are unknown. Here, we illustrate the total cumulative effects of income and age on evaluated well-being through all observed causal pathways based on a 1.6-million-observation global dataset and the structural causal model. This is the first study to investigate those casual relationships globally. We find that an increase in age always reduces evaluated well-being, and the adverse effects are aggravated with age. Furthermore, increased income continuously improves human well-being, but the impacts gradually become marginal with higher income. Our results demonstrate that physical health improvement in older people is the most effective way to intervene against the harmful effects of age on well-being. Moreover, increased income may dramatically enhance the well-being of people living close to the poverty line.
    DOI:  https://doi.org/10.1038/s41598-023-33235-7
  14. J Agric Food Chem. 2023 Apr 11.
    Urolithin A Produced by Novel Microbial Fermentation Possesses Anti-aging Effects by Improving Mitophagy and Reducing Reactive Oxygen Species in Caenorhabditis elegans.
    Mengwei Zhang, Shumao Cui, Bingyong Mao, Qiuxiang Zhang, Jianxin Zhao, Xin Tang, Wei Chen.
      Urolithin, intestinal microbiota metabolites of ellagitannin-rich foods, exhibit anti-aging activities. However, urolithin A is significantly superior to other types of urolithin with regard to this anti-aging function. This study aimed to screen edible urolithin A-producing strains of bacteria and explore the corresponding anti-aging efficacy of fermented products produced by these strains using Caenorhabditis elegans as a model. Our results showed that the Lactobacillus plantarum strains CCFM1286, CCFM1290, and CCFM1291 converted ellagitannin to produce urolithin A; the corresponding yields of urolithin A from these strains were 15.90 ± 1.46, 24.70 ± 0.82, and 32.01 ± 0.97 μM, respectively. Furthermore, it was found that the pomegranate juice extracts fermented by the CCFM1286, CCFM1290, and CCFM1291 strains of L. plantarum could extend lifespan by 26.04 ± 0.12, 32.05 ± 0.14, and 46.33 ± 0.12%, respectively, by improving mitochondrial function and/or reducing reactive oxygen species levels. These findings highlight the potential application of this fermentation in the subsequent development of anti-aging products.
    Keywords:  Lactobacillus plantarum; anti-aging; mitochondria; reactive oxygen species; urolithin A
    DOI:  https://doi.org/10.1021/acs.jafc.3c01062
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