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Unhealthy ageing poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the ageing process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, promoting healthy longevity in the old population. In response to the challenge of the ageing population and with a view to the future, Norway and the UK are fostering collaborations, supported by a "Money Follows Cooperation agreement" between the two nations. The inaugural Norway-UK joint meeting on ageing and dementia gathered leading experts on ageing and dementia from the two nations to share their latest discoveries in related fields. Since ageing is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular ageing mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (e.g., using NAD+ precursors). The meeting facilitated dialogue among policy makers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy ageing.

Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a “Money Follows Cooperation agreement” between the 2 nations. The inaugural Norway–UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging., Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a "Money Follows Cooperation agreement" between the 2 nations. The inaugural Norway-UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging.

Progeroid disorders are a heterogenous group of rare and complex hereditary syndromes presenting with pleiotropic phenotypes associated with normal aging. Due to the large variation in clinical presentation the diseases pose a diagnostic challenge for clinicians which consequently restricts medical research. To accommodate the challenge, we compiled a list of known progeroid syndromes and calculated the mean prevalence of their associated phenotypes, defining what we term the ‘progeria phenome’. The data were used to train a support vector machine that is available at https://www.mitodb.com and able to classify progerias based on phenotypes. Furthermore, this allowed us to investigate the correlation of progeroid syndromes and syndromes with various pathogenesis using hierarchical clustering algorithms and disease networks. We detected that ataxia-telangiectasia like disorder 2, spastic paraplegia 49 and Meier-Gorlin syndrome display strong association to progeroid syndromes, thereby implying that the syndromes are previously unrecognized progerias. In conclusion, our study has provided tools to evaluate the likelihood of a syndrome or patient being progeroid. This is a considerable step forward in our understanding of what constitutes a premature aging disorder and how to diagnose them., Progeroid disorders are a heterogenous group of rare and complex hereditary syndromes presenting with pleiotropic phenotypes associated with normal aging. Due to the large variation in clinical presentation the diseases pose a diagnostic challenge for clinicians which consequently restricts medical research. To accommodate the challenge, we compiled a list of known progeroid syndromes and calculated the mean prevalence of their associated phenotypes, defining what we term the ‘progeria phenome’. The data were used to train a support vector machine that is available at https://www.mitodb.com and able to classify progerias based on phenotypes. Furthermore, this allowed us to investigate the correlation of progeroid syndromes and syndromes with various pathogenesis using hierarchical clustering algorithms and disease networks. We detected that ataxia-telangiectasia like disorder 2, spastic paraplegia 49 and Meier-Gorlin syndrome display strong association to progeroid syndromes, thereby implying that the syndromes are previously unrecognized progerias. In conclusion, our study has provided tools to evaluate the likelihood of a syndrome or patient being progeroid. This is a considerable step forward in our understanding of what constitutes a premature aging disorder and how to diagnose them.

Cellular senescence, often defined as a state of permanent cell cycle arrest, is a complex and multifaceted process that arises in diverse contexts. First identified as the end point of replicative exhaustion [1], senescence also arises from DNA damage, mitochondrial dysfunction, oxidative stress, sustained mitogenic signaling through oncogenes, proteostatic stress and other. Senescence is under normal physiological conditions involved in wound healing and embryogenesis. Diverse processes trigger multiple mechanisms that converge into cell cycle arrest and a secretory phenotype. Two key pathways may lead to senescence, including the stress-associated p16/Rb pathway and the p53/p21 damage control mechanism. Senescence has been further characterized by its inflammatory secretome (SASP) that serves to signal immune clearance, although it differs by cell type and method of senescence induction. Despite its variable secretome, the SASP may better define senescence since nondividing cells including neurons and cardiomyocytes may exhibit senescent characteristics, despite being frozen at the G0/G1 stage in the cell cycle

ATP-citrate lyase is a central integrator of cellular metabolism in the interface of protein, carbohydrate, and lipid metabolism. The physiological consequences as well as the molecular mechanisms orchestrating the response to long-term pharmacologically induced Acly inhibition are unknown. We report here that the Acly inhibitor SB-204990 improves metabolic health and physical strength in wild-type mice when fed with a high-fat diet, while in mice fed with healthy diet results in metabolic imbalance and moderated insulin resistance. By applying a multiomic approach using untargeted metabolomics, transcriptomics, and proteomics, we determined that, in vivo, SB-204990 plays a role in the regulation of molecular mechanisms associated with aging, such as energy metabolism, mitochondrial function, mTOR signaling, and folate cycle, while global alterations on histone acetylation are absent. Our findings indicate a mechanism for regulating molecular pathways of aging that prevents the development of metabolic abnormalities associated with unhealthy dieting. This strategy might be explored for devising therapeutic approaches to prevent metabolic diseases.

DNA mismatch repair (MMR) is a highly conserved pathway that corrects both base–base mispairs and insertion-deletion loops (IDLs) generated during DNA replication. Defects in MMR have been linked to carcinogenesis and drug resistance. However, the regulation of MMR is poorly understood. Interestingly, CNOT6 is one of four deadenylase subunits in the conserved CCR4-NOT complex and it targets poly(A) tails of mRNAs for degradation. CNOT6 is overexpressed in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and androgen-independent prostate cancer cells, which suggests that an altered expression of CNOT6 may play a role in tumorigenesis. Here, we report that a depletion of CNOT6 sensitizes human U2OS cells to N-methyl-N′nitro-N-nitrosoguanidine (MNNG) and leads to enhanced apoptosis. We also demonstrate that the depletion of CNOT6 upregulates MMR and decreases the mutation frequency in MMR-proficient cells. Furthermore, the depletion of CNOT6 increases the stability of mRNA transcripts from MMR genes, leading to the increased expression of MMR proteins. Our work provides insight into a novel CNOT6-dependent mechanism for regulating MMR.

The risk of morbidity and mortality increases exponentially with age. Chronic inflammation, accumulation of DNA damage, dysfunctional mitochondria, and increased senescent cell load are factors contributing to this. Mechanistic investigations have revealed specific pathways and processes which, proposedly, cause age-related phenotypes such as frailty, reduced physical resilience, and multi-morbidity. Among promising treatments alleviating the consequences of aging are caloric restriction and pharmacologically targeting longevity pathways such as the mechanistic target of rapamycin (mTOR), sirtuins, and anti-apoptotic pathways in senescent cells. Regulation of these pathways and processes has revealed significant health- and lifespan extending results in animal models. Nevertheless, it remains unclear if similar results translate to humans. A requirement of translation are the development of age- and morbidity associated biomarkers as longitudinal trials are difficult and not feasible, practical, nor ethical when human life span is the endpoint. Current biomarkers and the results of anti-aging intervention studies in humans will be covered within this paper. The future of clinical trials targeting aging may be phase 2 and 3 studies with larger populations if safety and tolerability of investigated medication continues not to be a hurdle for further investigations., The risk of morbidity and mortality increases exponentially with age. Chronic inflammation, accumulation of DNA damage, dysfunctional mitochondria, and increased senescent cell load are factors contributing to this. Mechanistic investigations have revealed specific pathways and processes which, proposedly, cause age-related phenotypes such as frailty, reduced physical resilience, and multi-morbidity. Among promising treatments alleviating the consequences of aging are caloric restriction and pharmacologically targeting longevity pathways such as the mechanistic target of rapamycin (mTOR), sirtuins, and anti-apoptotic pathways in senescent cells. Regulation of these pathways and processes has revealed significant health- and lifespan extending results in animal models. Nevertheless, it remains unclear if similar results translate to humans. A requirement of translation are the development of age- and morbidity associated biomarkers as longitudinal trials are difficult and not feasible, practical, nor ethical when human life span is the endpoint. Current biomarkers and the results of anti-aging intervention studies in humans will be covered within this paper. The future of clinical trials targeting aging may be phase 2 and 3 studies with larger populations if safety and tolerability of investigated medication continues not to be a hurdle for further investigations.

Cells respond to many stressors by senescing, acquiring stable growth arrest, morphologic and metabolic changes, and a proinflammatory senescence-associated secretory phenotype. The heterogeneity of senescent cells (SnCs) and senescence-associated secretory phenotype are vast, yet ill characterized. SnCs have diverse roles in health and disease and are therapeutically targetable, making characterization of SnCs and their detection a priority. The Cellular Senescence Network (SenNet), a National Institutes of Health Common Fund initiative, was established to address this need. The goal of SenNet is to map SnCs across the human lifespan to advance diagnostic and therapeutic approaches to improve human health. State-of-the-art methods will be applied to identify, define and map SnCs in 18 human tissues. A common coordinate framework will integrate data to create four-dimensional SnC atlases. Other key SenNet deliverables include innovative tools and technologies to detect SnCs, new SnC biomarkers and extensive public multi-omics datasets. This Perspective lays out the impetus, goals, approaches and products of SenNet.