Oxidative stress, telomeres and cellular senescence: What non-drug interventions might break the link?

Telomeres are higher order structures that cap and protect chromosome ends. Telomeric DNA naturally shortens during somatic cell division and as a result of oxidative stress. Excessive shortening disrupts the integrity of the telomere, causing cellular senescence, one of the hallmarks of organismal ageing. The accumulation of senescent cells with ageing contributes to the loss of tissue homeostasis and the development of age-related pathologies. Hence, counteracting telomere shortening may be one relevant approach to develop strategies for healthier ageing. In this review I present the case for the existence of a link between oxidative stress, accelerated telomere shortening and cellular senescence. I also examine findings from human observational studies exploring associations between telomere length and oxidative stress-related parameters. Finally, I discuss results from randomised control trials testing the impact of non-pharmacological lifestyle interventions on the maintenance of telomere length, considering the potential mechanisms that might be involved

The use of the soluble receptor for advanced glycation-end products (sRAGE) as a potential biomarker of disease risk and adverse outcomes

The soluble receptor for advanced glycation end-products (sRAGE) has been classically considered a sink for pro-inflammatory RAGE ligands and as such has been associated with protection from inflammatory stress and disease. An alternative, though not mutually exclusive view is that high levels of sRAGE in circulation reflect the overstimulation of cell surface RAGE which if persistent, lead to the amplification of pro-inflammatory processes and the exacerbation of pathological states. With these two scenarios in mind this review focuses on the potential role of sRAGE as a prospective biomarker of disease risk and adverse outcomes

Short sleep duration is associated with shorter telomere length in healthy men: findings from the Whitehall II cohort study.

Shorter telomere length and poor sleep are more prevalent at older ages, but their relationship is uncertain. This study explored associations between sleep duration and telomere length in a sample of healthy middle and early old age people

Hostility and cellular aging in men from the Whitehall II cohort.

Hostility is associated with a significantly increased risk of age-related disease and mortality, yet the pathophysiological mechanisms involved remain unclear. Here we investigated the hypothesis that hostility might impact health by promoting cellular aging

COVID-19 and chronological aging : senolytics and other anti-aging drugs for the treatment or prevention of corona virus infection?

COVID-19, also known as SARS-CoV-2, is a new emerging zoonotic corona virus of the SARS (Severe Acute Respiratory Syndrome) and the MERS (Middle East Respiratory Syndrome) family. COVID-19 originated in China and spread world-wide, resulting in the pandemic of 2020. For some reason, COVID-19 shows a considerably higher mortality rate in patients with advanced chronological age. This begs the question as to whether there is a functional association between COVID-19 infection and the process of chronological aging. Two host receptors have been proposed for COVID-19. One is CD26 and the other is ACE-2 (angiotensin-converting enzyme 2). Interestingly, both CD26 and the angiotensin system show associations with senescence. Similarly, two proposed therapeutics for the treatment of COVID-19 infection are Azithromycin and Quercetin, both drugs with significant senolytic activity. Also, Chloroquine-related compounds inhibit the induction of the well-known senescence marker, Beta-galactosidase. Other anti-aging drugs should also be considered, such as Rapamycin and Doxycycline, as they behave as inhibitors of protein synthesis, blocking both SASP and viral replication. Therefore, we wish to speculate that the fight against COVID-19 disease should involve testing the hypothesis that senolytics and other anti-aging drugs may have a prominent role in preventing the transmission of the virus, as well as aid in its treatment. Thus, we propose that new clinical trials may be warranted, as several senolytic and anti-aging therapeutics are existing FDA-approved drugs, with excellent safety profiles, and would be readily available for drug repurposing efforts. As Azithromycin and Doxycycline are both commonly used antibiotics that inhibit viral replication and IL-6 production, we may want to consider this general class of antibiotics that functionally inhibits cellular protein synthesis as a side-effect, for the treatment and prevention of COVID-19 disease

Evaluation of economic effectiveness of the state purchases system : criteria and priorities

The purpose of the article is to develop new criteria and priorities of evaluating the economic effectiveness of the state purchases system in modern Russia. The methodology of the work consists of the general scientific methods (induction, deduction, formalization, synthesis, etc.) and specific methods of the economic theory. The authors conduct the problem analysis of the methodology of evaluation of economic effectiveness of the state purchases system which is applied in modern Russia and analyze the causal connections of its application in practice, as well as conduct the comparative analysis of this methodology and the specially developed proprietary method that allows eliminating the determined problems of the existing methodology. The authors conduct the criterial evaluation of economic effectiveness of the state purchases system in Russia with the specially developed method and conclude that the effectiveness of the state purchases system in modern Russia is high due to a large per cent of economy of budget assets, domination of orders for domestic products within the import substitution policy, stimulation of economic growth, and increase of the society’s well-being. Perspectives of further growth of its effectiveness according to the offered criteria and priorities are related to simplification of the procedures of applicants’ participation in auctions for stimulating their competition, increase of the share of electronic orders, and moderate reduction of the average sum of order.peer-reviewe

The longitudinal relationship between cortisol responses to mental stress and leukocyte telomere attrition

Context: Chronic psychological stress has been associated with shorter telomeres in some studies, but the underlying mechanisms are poorly understood. One possibility is that the neuroendocrine responses associated with stress exposure are involved. Objective: To testing the hypothesis that greater cortisol responsivity to acute stressors predicts more rapid telomere attrition. Design: We measured salivary cortisol responses to two challenging behavioral tasks. Leukocyte telomere length was measured at the time of mental stress testing and 3 years later. Participants: We studied 411 initially healthy men and women aged 54-76 years. Main outcome measure: Leukocyte telomere length. Results: Cortisol responses to this protocol were small, we divided participants into cortisol responders (n = 156) and non-responders (n = 255) using a criterion (≥20%) previously shown to predict increases in cardiovascular disease risk. There was no significant association between cortisol responsivity and baseline telomere length, although cortisol responders tended to have somewhat shorter telomeres (β = -0.061, standard error 0.049). But cortisol responders had shorter telomeres and more rapid telomere attrition than non-responders on follow-up, after controlling statistically for age, gender, socioeconomic status, smoking, time of day of stress testing and baseline telomere length (β = -0.10, standard error 0.046, p = 0.029). The association was maintained after additional control for cardiovascular risk factors (β = -0.11, p = 0.031). The difference between cortisol responders and non-responders was equivalent to approximately 2 years in aging. Conclusions: These findings suggest that cortisol responsivity may mediate in part the relationship between psychological stress and cellular aging

Short sleep duration is associated with shorter telomere length in healthy men: findings from the Whitehall II cohort study

Background: Shorter telomere length and poor sleep are more prevalent at older ages, but their relationship is uncertain. This study explored associations between sleep duration and telomere length in a sample of healthy middle and early old age people. Methods: Participants were 434 men and women aged 63.3 years on average drawn from the Whitehall II cohort study. Sleep duration was measured by self-report. Results: There was a linear association between sleep duration and leukocyte telomere length in men but not in women (P = 0.035). Men reporting shorter sleep duration had shorter telomeres, independently of age, body mass index, smoking, educational attainment, current employment, cynical hostility scores and depressive symptoms. Telomeres were on average 6% shorter in men sleeping 5 hours or fewer compared with those sleeping more than 7 hours per night. Conclusion: This study adds to the growing literature relating sleep duration with biomarkers of aging, and suggests that shortening of telomeres might reflect mechanisms through which short sleep contributes to pathological conditions in older men

Nitric oxide availability is increased in contracting skeletal muscle from aged mice, but does not differentially decrease muscle superoxide

Reactive oxygen and nitrogen species have been implicated in the loss of skeletal muscle mass and function that occurs during aging. Nitric oxide (NO) and superoxide are generated by skeletal muscle and where these are generated in proximity their chemical reaction to form peroxynitrite can compete with the superoxide dismutation to hydrogen peroxide. Changes in NO availability may therefore theoretically modify superoxide and peroxynitrite activities in tissues, but published data are contradictory regarding aging effects on muscle NO availability. We hypothesised that an age-related increase in NO generation might increase peroxynitrite generation in muscles from old mice, leading to an increased nitration of muscle proteins and decreased superoxide availability. This was examined using fluorescent probes and an isolated fiber preparation to examine NO content and superoxide in the cytosol and mitochondria of muscle fibers from adult and old mice both at rest and following contractile activity. We also examined the 3-nitrotyrosine (3-NT) and peroxiredoxin 5 (Prx5) content of muscles from mice as markers of peroxynitrite activity. Data indicate that a substantial age-related increase in NO levels occurred in muscle fibers during contractile activity and this was associated with an increase in muscle eNOS. Muscle proteins from old mice also showed an increased 3-NT content. Inhibition of NOS indicated that NO decreased superoxide bioavailability in muscle mitochondria, although this effect was not age related. Thus increased NO in muscles of old mice was associated with an increased 3-NT content that may potentially contribute to age-related degenerative changes in skeletal muscle