Thomas Von Zglinicki

Introduction Metformin has pleiotropic biological effects which might improve muscle function in older people. The MET-PREVENT trial tested the efficacy and safety of metformin as a therapy for sarcopenia and frailty in older people. Methods Double blind, randomised, parallel-group, placebo-controlled trial. Participants aged ≥65 with walk speed <0.8m/s and low muscle strength (handgrip <16kg for women, <27kg for men, or 5x sit to stand >15s) were recruited from primary care and hospital clinics. Participants were randomised 1:1 using a web-based interactive system to receive 4 months of 500mg metformin or matching placebo 3x/day. The primary outcome, analysed by intention to treat, was the between-group difference in 4m walk speed at 4 months, adjusted for baseline values. Secondary outcomes included grip strength, short physical performance battery, six-minute …

Anti-senescence interventions are exceptionally effective in alleviating a wide range of age-associated diseases and disabilities. However, the sensitivity and specificity of current senolytic interventions are limited. Mitochondrial dysfunction is an integral part of the senescent phenotype and we demonstrate that specific loss of complex I-linked coupled respiration and the inability to maintain mitochondrial membrane potential upon respiratory stimulation are early and persistent features in a cell's progression towards senescence. We thus identify senescence-associated mitochondrial dysfunction as a targetable vulnerability of senescent cells and show that further decreasing mitochondrial membrane potential of senescent cells with a low concentration of a mitochondrial uncoupler synergistically enhances the in vitro senolytic efficacy of BH3 mimetic drugs, including Navitoclax, by up two orders of magnitude. Moreover, in an in vivo mouse model of radiation-induced premature ageing, we show that a short-term intervention combining the mitochondrial uncoupler BAM15 with Navitoclax at a dose two orders of magnitude lower than typically used reduces frailty and improves cognitive function for at least 8 months after irradiation. Therefore our study shows that compromised mitochondrial functional capacity is a specific vulnerability of senescent cells which can be targeted by mild uncoupling in vitro and in vivo.

High-grade gliomas are primary brain tumors that are incredibly refractory long-term to surgery and chemoradiation, with no proven durable salvage therapies for patients that have failed conventional treatments. Post-treatment, the latent glioma and its microenvironment are characterized by a senescent-like state of mitotic arrest and a senescence-associated secretory phenotype (SASP) induced by prior chemoradiation. Although senescence was once thought to be irreversible, recent evidence has demonstrated that cells may escape this state and re-enter the cell cycle, contributing to tumor recurrence. Moreover, senescent tumor cells could spur the growth of their non-senescent counterparts, thereby accelerating recurrence. In this review, we highlight emerging evidence supporting the use of senolytic agents to ablate latent, senescent-like cells that could contribute to tumor recurrence. We also discuss how …

Senescence is a complex cellular reaction to stress involving a prolonged DNA damage response, proliferation arrest, reprogramming of the epigenome, secretion of a wide array of bioactive molecules, mitochondrial dysfunction and profound changes in response to nutrient signaling and in auto- and mitophagy. These components or building blocks are interlinked in a system of feedback loops that stabilize the senescent phenotype. Senescent cells accumulate in most tissues, including postmitotic ones during aging and contribute to reduced regenerative capacity, chronic inflammation, and metabolic decline. Pharmacologic interventions that specifically ablate senescent cells (senolytics) or suppress the senescent phenotype (senostatics) have the potential to relieve a wide range of age-associated degenerative diseases, disabilities and frailty.

Aging is a gradual, continuous series of natural changes in biological, physiological, immunological, environmental, psychological, behavioral, and social processes. Aging entails changes in the immune system characterized by a decrease in thymic output of naïve lymphocytes, an accumulated chronic antigenic stress notably caused by chronic infections such as cytomegalovirus (CMV), and immune cell senescence with acquisition of an inflammatory senescence-associated secretory phenotype (SASP). For this reason, and due to the SASP originating from other tissues, aging is commonly accompanied by low-grade chronic inflammation, termed “inflammaging”. After decades of accumulating evidence regarding age-related processes and chronic inflammation, the domain now appears mature enough to allow an integrative reinterpretation of old data. Here, we provide an overview of the topics discussed in a …

Increasingly unparalleled changed in global demographics mean that there is now an even greater need for research focused on ageing; it is estimated that 1 in 6 people will be over 65 in the year 2050. The health and integrity of skin is imperative to general health and wellbeing. However, the unique experience of skin as the barrier to the external environment leads to constant exposure to exogenous stressors, extrinsic ageing, as well as the usual impacts of chronological or intrinsic ageing. In turn, these sustained assaults induce pathological changes in skin structure and function, yet there are few in vitro human skin equivalents (HSEs) which can accurately recapitulate the complex nature of ageing skin. Utilizing a previously established HSE, we have bioengineered full thickness skin tissues which encapsulate various aspects of ageing skin through including senescent cells and fibroblasts/keratinocytes from …

Senescence is a cellular aging-related process triggered by different stresses and characterized by the secretion of various inflammatory factors referred to as the senescence-associated secretory phenotype (SASP). Here, we present evidence that the inflammasome sensor, NLRP1, is a key mediator of senescence induced by irradiation both in vitro and in vivo. The NLRP1 inflammasome promotes senescence by regulating the expression of p16, p21, p53, and SASP in Gasdermin D (GSDMD)-dependent manner as these responses are reduced in conditions of NLRP1 insufficiency or GSDMD inhibition. Mechanistically, the NLRP1 inflammasome is activated downstream of the cytosolic DNA sensor cGMP-AMP (cGAMP) synthase (cGAS) in response to genomic damage. These findings provide a rationale for inhibiting the NLRP1 inflammasome-GSDMD axis to treat senescence-driven disorders.

Introduction Skeletal muscle dysfunction is central to both sarcopenia and physical frailty, which are associated with a wide range of adverse outcomes including falls and fractures, longer hospital stays, dependency and the need for care. Resistance training may prevent and treat sarcopenia and physical frailty, but not everyone can or wants to exercise. Finding alternatives is critical to alleviate the burden of adverse outcomes associated with sarcopenia and physical frailty. This trial will provide proof-of-concept evidence as to whether metformin can improve physical performance in older people with sarcopenia and physical prefrailty or frailty. Methods and analysis MET-PREVENT is a parallel group, double-blind, placebo-controlled proof-of-concept trial. Trial participants can participate from their own homes, including completing informed consent and screening assessments. Eligible participants with low grip …

Mitochondrial dysfunction and cell senescence are hallmarks of aging and are closely interconnected. Mitochondrial dysfunction, operationally defined as a decreased respiratory capacity per mitochondrion together with a decreased mitochondrial membrane potential, typically accompanied by increased production of oxygen free radicals, is a cause and a consequence of cellular senescence and figures prominently in multiple feedback loops that induce and maintain the senescent phenotype. Here, we summarize pathways that cause mitochondrial dysfunction in senescence and aging and discuss the major consequences of mitochondrial dysfunction and how these consequences contribute to senescence and aging. We also highlight the potential of senescence-associated mitochondrial dysfunction as an antiaging and antisenescence intervention target, proposing the combination of multiple interventions …

Selective degradation of damaged mitochondria by autophagy (mitophagy) is proposed to play an important role in cellular homeostasis. However, the molecular mechanisms and the requirement of mitochondrial quality control by mitophagy for cellular physiology are poorly understood. Here we demonstrated that primary human skin fibroblasts in cell culture maintain highly active basal mitophagy driven by mitochondrial ROS signalling. Mitophagy was found to be mediated by PINK1/Parkin-dependent pathway involving p62 as a selective autophagy receptor. Importantly, this pathway was disturbed upon the induction of cellular senescence leading to a robust shutdown of mitophagy. Suppression of mitophagy was sufficient to trigger the senescence programme, whilst re-activation of mitophagy was necessary for anti-senescence effects of NAD precursors or rapamycin. Furthermore, activation of mitophagy by a p62-targeting small molecule suppressed markers of senescence establishing mitochondrial quality control as a promising target for the development of novel anti-ageing interventions.

Introduction Immunosenescence, a decline in immune system function, has been linked to several age-related diseases and geriatric syndromes, including cardiovascular diseases and frailty. Very old adults (aged ≥85 years) live with multiple long-term conditions (MLTC) or multimorbidity—a complex phenomenon of poor health defined by either counts (≥2 diseases), indices, or patterns. However, little is known about the relationship between immunosenescence and MLTC in this age group. We utilised baseline data from the Newcastle 85+ Study to investigate the association between previously defined immunosenescence profilesa and MLTC. Method We used data from 703 participants who had multimorbidity and complete data for 16 chronic diseases and geriatric syndromes (i.e. analytic sample). MLTC counts were derived from the number of conditions and …

Frailty is a major risk factor in aging which affects individuals' life quality and health conditions at old age, increasing their vulnerability to stresses and the incidence for morbidity and mortality. However, the fundamental cause(s) of frailty are still unclear.Evidence from correlative and intervention studies is accumulating which suggests cell senescence as a major and physiologically relevant cause of frailty in mice and possibly humans. After introducing the concept of frailty and its operationalization, we review the evidence for and against a causal role of cell senescence. We find that most of the evidence is in line with the hypothesis that senescence is an important cause of frailty, particularly the results from senescent cell transplantation studies and senolytic studies in mice. However, there are essential limitations: previous intervention studies are limited to mice and have not used comprehensive frailty …

Cancer survivors suffer from progressive frailty, multimorbidity, and premature morbidity. We hypothesise that therapy-induced senescence and senescence progression via bystander effects are significant causes of this premature ageing phenotype. Accordingly, the study addresses the question whether a short anti-senescence intervention is able to block progression of radiation-induced frailty and disability in a pre-clinical setting. Male mice were sublethally irradiated at 5 months of age and treated (or not) with either a senolytic drug (Navitoclax or dasatinib+ quercetin) for 10 days or with the senostatic metformin for 10 weeks. Follow-up was for 1 year. Treatments commencing within a month after irradiation effectively reduced frailty progression (p< 0.05) and improved muscle (p< 0.01) and liver (p< 0.05) function as well as short-term memory (p< 0.05) until advanced age with no need for repeated interventions. Senolytic interventions that started late, after radiation-induced premature frailty was manifest, still had beneficial effects on frailty (p< 0.05) and short-term memory (p< 0.05). Metformin was similarly effective as senolytics. At therapeutically achievable concentrations, metformin acted as a senostatic neither via inhibition of mitochondrial complex I, nor via improvement of mitophagy or mitochondrial function, but by reducing nonmitochondrial reactive oxygen species production via NADPH oxidase 4 inhibition in senescent cells. Our study suggests that the progression of adverse long-term health and quality-of-life effects of radiation exposure, as experienced by cancer survivors, might be rescued by short-term adjuvant anti-senescence …

Immunosenescence, a decline in immune system function, has been linked to several age-related diseases and ageing syndromes. Very old adults (aged ≥ 85 years) live with multiple long-term conditions (MLTC, also known as multimorbidity)—a complex phenomenon of poor health defined by either counts, indices, or patterns, but little is known about the relationship between an ageing immune system and MLTC in this age group. We utilised baseline data from the Newcastle 85+ Study to investigate the associations between previously defined immunosenescence profiles of lymphocyte compartments and MLTC counts and patterns (from 16 chronic diseases/ageing syndromes). Seven hundred and three participants had MLTC and complete data for all 16 conditions, a median and mean of 5 (range 2–11) and 62.2% had ≥ 5 conditions. Three distinct MLTC patterns emerged by clustering: Cluster 1 (‘Low …

This chapter describes the mechanisms of cellular deterioration and their relevance to organ and organismal function, along with implications for healthy ageing and successful treatment. An 'old cell' is one that has reached or is close to reaching the end of its replicative cycle - that is, is nearly or fully senescent. Even in the oldest individuals, most of the cells will not have reached this state and should still be considered young cells. Senescent cells accumulate with age in multiple organs and may therefore lead to deterioration through the autonomous depletion of functional cells. Cell senescence is clearly such a trait: it is beneficial as it prevents cells from becoming neoplastic; however, as senescent cells increase with age, the bystander effects become increasingly important in stimulating the malignancy of other cells, as well as contributing to organismal decline.

The ageing global demographic constantly reinforces the need for more age focussed research, in order to better support the population to live healthier for longer. As the interface between the human body and the external environment, the experience of skin is unique, being subjected to both internal and external ageing influences, leading to pathological changes in structure/function. Currently, there are few in vitro ageing skin equivalents to undertake this research, and even fewer which account for both ageing factors. The presence of senescent cells within the dermis is well established, but what is their role in influencing epidermal behavior and morphology and how do they interact with intrinsically aged cells? Modifying an established in vitro human skin model which utilizes scaffold technology, we have combined senescent cells with various primary skin cell populations to recapitulate the structure and …

Human skin ageing is a complex and heterogeneous process, which is influenced by genetically determined intrinsic factors and accelerated by cumulative exposure to extrinsic stressors. In the current world ageing demographic, there is a requirement for a bioengineered ageing skin model, to further the understanding of the intricate molecular mechanisms of skin ageing, and provide a distinct and biologically relevant platform for testing actives and formulations. There have been many recent advances in the development of skin models that recapitulate aspects of the ageing phenotype in vitro. This review encompasses the features of skin ageing, the molecular mechanisms that drive the ageing phenotype, and tissue engineering strategies that have been utilised to bioengineer ageing skin in vitro.

IntroductionSkeletal muscle dysfunction is central to both sarcopenia and physical frailty, which are associated with a wide range of adverse outcomes including falls and fractures, longer hospital stays, dependency and the need for care. Resistance training may prevent and treat sarcopenia and physical frailty, but not everyone can or wants to exercise. Finding alternatives is critical to alleviate the burden of adverse outcomes associated with sarcopenia and physical frailty. This trial will provide proof-of-concept evidence as to whether metformin can improve physical performance in older people with sarcopenia and physical prefrailty or frailty.Methods and analysisMET-PREVENT is a parallel group, double-blind, placebo-controlled proof-of-concept trial. Trial participants can participate from their own homes, including completing informed consent and screening assessments. Eligible participants with low grip …

Cellular senescence is characterized by an irreversible cell cycle arrest as well as a pro‐inflammatory phenotype, thought to contribute to aging and age‐related diseases. Neutrophils have essential roles in inflammatory responses; however, in certain contexts their abundance is associated with a number of age‐related diseases, including liver disease. The relationship between neutrophils and cellular senescence is not well understood. Here, we show that telomeres in non‐immune cells are highly susceptible to oxidative damage caused by neighboring neutrophils. Neutrophils cause telomere dysfunction both in vitro and ex vivo in a ROS‐dependent manner. In a mouse model of acute liver injury, depletion of neutrophils reduces telomere dysfunction and senescence. Finally, we show that senescent cells mediate the recruitment of neutrophils to the aged liver and propose that this may be a mechanism by …

Naked mole‐rats express many unusual traits for such a small rodent. Their morphology, social behaviour, physiology, and ageing have been well studied over the past half‐century. Many early findings and speculations about this subterranean species persist in the literature, although some have been repeatedly questioned or refuted. While the popularity of this species as a natural‐history curiosity, and oversimplified story‐telling in science journalism, might have fuelled the perpetuation of such misconceptions, an accurate understanding of their biology is especially important for this new biomedical model organism. We review 28 of these persistent myths about naked mole‐rat sensory abilities, ecophysiology, social behaviour, development and ageing, and where possible we explain how these misunderstandings came about.