Ageing research in model organisms has led to the rapid discovery and genetic dissection of key ageing pathways, including the RAS/MAPK signalling pathway. Genetic interventions that modulate signalling through RAS proteins and their downstream effectors have been shown to increase lifespan in these model systems and to improve multiple parameters of health, both during normal ageing and in animal models of age-related disease. RAS/MAPK signalling therefore adds to an emerging theme that manipulating cancer-promoting pathways, either by inhibiting the function of oncogenes or by increasing the activity of tumour suppressors, can affect healthy ageing.

Examples from rodent models that extend lifespan include Myc haploinsufficiency, extra genomic copies of the Ink4/Arf locus, that elevate expression of its encoded tumour suppressor proteins p16 and p14, and increased gene dosage of the tumour suppressor Pten, or mimicking its activation through genetic inhibition of its direct target, PI3K. Interestingly, although some these models had reduced cancer incidence, researchers also observed lifespan extension in cancer-free animals, suggesting that delayed ageing may not simply be a consequence of protection against cancer.

The prominent role of RAS/MAPK signalling in cancer has led to the isolation of several small molecule inhibitors of the pathway, and some are already in clinical use. Recent work with model organisms suggests that these same compounds may provide beneficial effects on age-related health. Thus, repurposing these anti-cancer treatments could provide a useful strategy to develop novel interventions to promote healthy ageing. Moreover, other pro-longevity pharmacological interventions may elicit their effects on ageing and age-related health, at least in part through perturbations in RAS/MAPK signal transduction. It should be noted, though, that compounds like metformin, acarbose, dihydromyricetin, and statins have much broader effects, and, although they have an impact on RAS/MAPK outputs, they do not exclusively target this pathway.

However, cancer therapeutics, including small molecule inhibitors of RAS/MAPK signalling, are notoriously toxic and can elicit severe side effects. Effective strategies to limit these adverse effects will therefore be essential for clinical implementation. Determining the critical time periods during the life course when RAS/MAPK inhibition modulates ageing, and assessing the effect of intermittent dosing, could be one such approach to minimise side effects. Careful titration will also help to provide the geroprotective effects of these drugs without side effects or drug resistance.

Since the discovery of GDF11 as a "youth factor", it has become a "hot" molecule in the field of anti-aging study. Yet there is still controversy over the age-related change in concentration of GDF11 and its role in the genesis of rejuvenation conditions. With the aid of a highly specific anti-GDF11 antibody, here we show that GDF11 concentration declines with age in male mice, confirming the results of ours and others that blood GDF11 abundance reduces with age in both fish and mouse as well as humans.

In this study, we displayed rGDF11 on the surface of the yeast Yarrowic Lipolytica, and proved the bioavailability of the yeast-displayed rGDF11 by oral delivery in aged male mice. On the basis of these findings, we started to explore the anti-aging activity and underlying mechanisms of displayed rGDF11. It was found that dietary intake of displayed rGDF11 had little influence on the body weight and biochemical parameters of aged male mice, but delayed the occurrence and development of age-related biomarkers such as lipofuscin and senescence-associated-β-galactosidase, and to some extent, prolonged the lifespan of aged male mice.

Moreover, we demonstrated once again that dietary intake of displayed rGDF11 enhanced the activity of anti-oxidant enzymes, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPX), reduced the reactive oxygen species (ROS) level, and slowed down the protein oxidation and lipid peroxidation. Importantly, we showed for the first time that rGDF11 enhanced the activity of CAT, SOD, and GPX through activation of the Smad2/3 signaling pathway. Our study also provided a simple and safe route for delivery of recombinant GDF11, facilitating its therapeutic application in the future.

When stressed, damaged or dysfunctional, mitochondria expel their DNA (mtDNA), oxidized and cleaved, into the cytosol - the fluid within a cell in which organelles float - and beyond into the bloodstream, triggering inflammation. In autoimmune conditions like lupus and rheumatoid arthritis, the amounts of circulating oxidized mtDNA correlate with disease severity, flare-ups, and how well patients respond to therapies. An unanswered question that has plagued the field is whether oxidized mtDNA is simply a biomarker or indicator of disease or something more: a critical player in disease pathology.

In a new study, researchers describe the biochemical pathway that results in the generation of oxidized mtDNA, how it is expelled by mitochondria and how it triggers the complex and destructive inflammatory response that follows. "In addition to charting a new pathway responsible for the generation of inflammation-provoking fragments of oxidized mtDNA, this work opens the door to the development of new anti-inflammatory agents."

Mitochondrial DNA (mtDNA) that escapes from stressed mitochondria acts to provoke inflammation via cGAS-STING pathway activation and, when oxidized (Ox-mtDNA), it binds cytosolic NLRP3, thereby triggering inflammasome activation. However, it is unknown how and in which form Ox-mtDNA exits stressed mitochondria in non-apoptotic macrophages. We found that diverse NLRP3 inflammasome activators rapidly stimulated uniporter-mediated calcium uptake to open mitochondrial permeability transition pores (mPTP) and trigger VDAC oligomerization. This occurred independently of mtDNA or reactive oxygen species, which induce Ox-mtDNA generation.

Within mitochondria, Ox-mtDNA was either repaired by DNA glycosylase OGG1 or cleaved by the endonuclease FEN1 to 500-650 base pair fragments that exited mitochondria via mPTP- and VDAC-dependent channels to initiate cytosolic NLRP3 inflammasome activation. Ox-mtDNA fragments also activated cGAS-STING signaling and gave rise to pro-inflammatory extracellular DNA. Understanding this process will advance the development of potential treatments for chronic inflammatory diseases, exemplified by FEN1 inhibitors that suppressed interleukin-1β (IL-1β) production and mtDNA release in mice.

Life tables summarise a population's mortality experience during a time period. Sex- and age-specific life tables are needed to compute various cancer survival measures. However, mortality rates vary according to socioeconomic status. We present sex- and age-specific life tables based on socioeconomic status at the census tract level in Spain during 2011-2013 that will allow estimating cancer relative survival estimates and life expectancy measures by socioeconomic status.

Life expectancy (LE) at birth was higher among women than among men. Women and men in the most deprived census tracts in Spain lived 3.2 and 3.8 years less than their counterparts in the least deprived areas. Overall, we found a consistent LE gap at birth according to socioeconomic status for both sexes in Spain during the 2011-2013 period. However, the gap was wider among men than among women, with the least deprived male group experiencing shorter LE at birth than the most deprived female group. Furthermore, we found a geographical pattern characterised by shorter LE at birth in the southwest for both sexes in Spain.

Furthermore, our results on LE at birth by deprivation are consistent with those of other European studies. In the UK, LE at birth in 2005 presented a similar pattern, with the highest LE in the most affluent groups compared to the most deprived group, with a gap between 2.7 and 5.0 years for males and between 2.5 and 3.6 years for females. Overall, differences in LE are seen by deprivation and by region, and the regions with higher LE are also the least deprived. Similar to the geographical pattern found in Spain, a regional pattern characterised by a clear north-south gradient was found in the UK, with deprivation explaining most of the geographical variation in LE.

In a study of the relative effects of genetics, aging, and the environment on how some 20,000 human genes are expressed, the researchers found that aging and environment are far more important than genetic variation in affecting the expression profiles of many of our genes as we get older. The level at which genes are expressed - that is, ratcheted up or down in activity - determines everything from our hormone levels and metabolism to the mobilization of enzymes that repair the body.

while our individual genetic makeup can help predict gene expression when we are younger, it is less useful in predicting which genes are ramped up or down when we're older - in this study, older than 55 years. Identical twins, for example, have the same set of genes, but as they age, their gene expression profiles diverge, meaning that twins can age much differently from each other. The findings have implications for efforts to correlate diseases of aging with genetic variation in humans. Such studies should perhaps focus less on genetic variants that impact gene expression when pursuing drug targets.

The findings are in line with Medawar's hypothesis: Genes that are turned on when we are young are more constrained by evolution because they are critical to making sure we survive to reproduce, while genes expressed after we reach reproductive age are under less evolutionary pressure. So, one would expect a lot more variation in how genes are expressed later in life. "Across all the tissues in your body, genetics matters about the same amount. It doesn't seem like it plays more of a role in one tissue or another tissue. But aging is vastly different between different tissues. In your blood, colon, arteries, esophagus, fat tissue, age plays a much stronger role than your genetics in driving your gene expression patterns."

Overall this work has several important implications. Our results shed light on recent work on the prediction accuracy of polygenic risk scores (PRS) which found that numerous factors, including age, sex, and socioeconomic status can profoundly impact the prediction accuracy of such scores even in individuals with the same genetic ancestry. Our results highlight that genetics exhibit varied predictive power in several different tissues as a function of age, potentially playing a role in differential PRS accuracy between young and old individuals.

This also has important implications for disease association and prediction approaches that leverage expression quantitative trait loci (eQTLs) to prioritize variants. If a significant proportion of eQTLs exhibit age-associated biases in their effect size in a tissue of interest, then these approaches may be less powerful when applied to diseases for which age is a primary risk factor such as heart disease, Alzheimer's disease, cancers, and diabetes.

DNA damage can activate Ataxia telangiectasia-mutated serine/threonine kinase (ATM) and Rad3-related serine/threonine kinase (ATR), after which p53 activates p21, stopping the cell cycle and inducing cell senescence. GATA4 is a transcription factor that regulates signal response processes in many organs, such as cardiac precursor cell differentiation, cardiac development, cardiac hypertrophy, and resistance to apoptosis, as well as mediating the effects of genetic mutations caused by congenital heart disease.

GATA4 regulates proteins in a context-dependent manner, thereby performing multiple functions. It has been reported that GATA4 is regulated upstream by the DNA damage response (DDR) pathway co-opting ATM and ATR, and downstream in a manner different from the conventional DDR pathway, leading to senescence. GATA4 is regulated by ATM and ATR, which inhibit the binding of p62 and GATA4 to inhibit selective lineage autophagy of GATA4, thereby activating NF-κB, leading to cellular senescence. In addition, alterations in the GATA4 signaling pathway have been frequently observed in various age-related diseases, including atherosclerosis and heart failure.

This paper reviews the mechanisms through which the DDR signaling pathway leads to cellular senescence, the involvement of the GATA4 factor in these processes, as well as the link to atherosclerosis and heart failure. This provides many possibilities to invent a drug to inhibit GATA4 activity and thereby prevent cell senescence, but there are still many problems to be solved.

Individual conditions have been identified as risk factors for dementia; however, it is important to consider the role of multimorbidity, as conditions often co-occur. This study investigated whether multimorbidity is associated with incident dementia and whether associations vary by different clusters of disease and genetic risk for dementia. The study used data from the UK Biobank cohort, with baseline data collected between 2006 and 2010 and with up to 15 years of follow-up. Participants included women and men without dementia and aged at least 60 years at baseline. The presence of at least 2 long-term conditions from a preselected list of 42 conditions was used to define multimorbidity.

A total of 206,960 participants (mean age 64.1 years) were included in the final sample, of whom 89,201 participants (43.1%) had multimorbidity. Over a mean of 11.8 years of follow-up, 6,182 participants (3.0%) developed dementia. The incidence rate was 1.87 per 1,000 person-years for those without multimorbidity and 3.41 per 1,000 person-years for those with multimorbidity. In Cox proportional hazards models adjusted for age, sex, ethnicity, education, socioeconomic status, and APOE-ε4 carrier status, multimorbidity was associated with an increased risk of incident dementia (hazard ratio [HR], 1.63).

The highest dementia risk was observed for the hypertension, diabetes, and coronary heart disease cluster (HR 2.20) and pain, osteoporosis, and dyspepsia cluster (HR 2.00) in women and in the diabetes and hypertension cluster (HR 2.24) and coronary heart disease, hypertension, and stroke cluster (HR 1.94) in men, compared with no multimorbidity. The associations between multimorbidity and dementia were greater in those with a lower genetic risk of dementia (HR 1.96) than in those with a higher genetic risk of dementia (HR 1.39). Similar findings were observed when stratifying diseases clusters by genetic risk for dementia.

Key support for the toxic amyloid hypothesis comes from the observation that mutations in any of three genes (APP, PSEN1, and PSEN2) lead to Alzheimer's disease (AD). The genetic evidence causally implicates the fibrillogenic 42-amino acid amyloid-β peptide (Aβ42). However, the disease pathogenesis may arise from either of two ends of the protein aggregation process: the increase in insoluble amyloid plaques or the depletion of the soluble Aβ42 peptide, which has important functions. While insoluble amyloid plaques can be present in normal individuals, low soluble levels of Aβ42 are an invariable feature of AD.

The hypothesis of Aβ toxicity has traditionally been supported by the notion that AD-causing mutation carriers must have high levels of soluble Aβ42 relative to non-mutation populations. In fact, mutation carriers have lower Aβ42 levels compared to non-mutation populations. The reduction in soluble Aβ42 levels among mutation carriers begins as many as 25 years before the onset of cognitive symptoms. Therefore, the toxicity in the process of accelerated protein aggregation among mutation carriers may conceivably be due to the depletion in soluble Aβ42 to a greater extent than the corresponding increase in amyloid. This alternative hypothesis offers an explanation for the failures in translating amyloid reduction into cognitive improvement, even among mutation carriers, and for the paradoxes posed by the large proportion of amyloid-positive individuals without dementia and even of centenarians without history of cognitive abnormalities, half of whom have autopsy-confirmed AD pathology.

We recently observed that among amyloid positron emission tomography (PET)-positive individuals, higher levels of soluble Aβ42 were associated with normal cognition and brain volumes in all tertiles of brain amyloidosis, with an effect size greater than that of increases in brain amyloid burden.

Alzheimer's disease (AD) is a complex disorder that is clinically characterized by the progressive decline in cognition, and pathologically characterized by the accumulation of amyloid-β (Aβ) and phosphorylated tau (P-tau) in the brain. In recent years, a series of studies have demonstrated that AD is linked to blood brain barrier (BBB) dysfunction. BBB dysfunction has been identified in the early stage of AD. The BBB is a continuous membrane formed by a tightly sealed monolayer of endothelial cells. The main function of the BBB is maintenance of the brain health micro-environment by keeping neurotoxic components, pathogens, and circulating blood out of the brain.

The first clues regarding BBB dysfunction came from studies performed in AD genetic animal models with Aβ or tau pathology. Therefore, at that time, it was believed that BBB dysfunction was associated with Aβ or tau pathology. However, BBB breakdown and vascular dysregulation were also determined in preclinical and early-stage AD patients before cognitive decline or positive Aβ and tau pathology. These results suggested that the BBB breakdown that appeared in the early stage of AD could not be fully explained by the consequence of Aβ and/or tau pathology (the forms of plaques, tangles, and oligomers).

In recent years, emerging evidence has supported the contributions of neuroinflammation to AD pathogenesis. The associations between BBB breakdown and neuroinflammation have been explored in several studies. An injured BBB was associated with neuroinflammation such as microglial activation and elevated inflammatory cytokines release. However, the exact role of BBB dysfunction in AD pathogenesis is still unknown. It remains elusive whether BBB dysfunction is a consequence or a cause of Aβ pathology, tau pathology, neuroinflammation, or other conditions.

Abdominal aortic aneurysm (AAA) is locally weak and aneurysm-like dilatation of the abdominal aorta, with a diameter of 3 cm or more, more than 1.5 times the normal diameter AAA is a common disease among the elderly, and the incidence of AAA increases with age. Most AAA patients are asymptomatic and are discovered accidentally during a physical exam or ultrasound screening. However, rupture or precursor rupture may occur when patients present with symptoms such as lumbago and abdominal pain. The in-hospital mortality rate of rupture is about 40%, while the out-of-hospital mortality rate can be as high as 90%, resulting in about 150,000-200,000 deaths globally per year.

The threat of AAA mainly in elderly patients is becoming more and more serious. Currently there is no effective method to inhibit AAA progress via treatment with clinical drug. Thus it is of great clinical significance to study the pathogenesis of AAA and explore potential therapeutic targets. The purpose of this paper is to analyze the pathogenesis of AAA from the perspective of cellular senescence: on the basis of clear evidence of cellular senescence in aneurysm wall, we actively elucidate specific molecular and regulatory pathways, and to explore the targeted drugs related to senescence and senescent cell elimination measures, eventually improve the health of patients with AAA and prolong the life of human beings.

Centrophenoxine (CPH) is a compound consisting of dimethylaminoethanol (DMAE) and para-chlorophenoxyacetic acid (pCPA), joined by a chemical bond. DMAE can be converted by cells into choline, which is a precursor of membrane phospholipids, neurotransmitters, and other important biomolecules. The pCPA component enhances the penetration of CPH across the blood-brain barrier. CPH supplementation is hypothesized to increase brain acetylcholine levels, protect neurons from oxidative damage, improve cognitive function, and reduce age-related lipofuscin accumulation.

There is moderate evidence that centrophenoxine may benefit patients hospitalized for injury to the brain from either vascular or traumatic origin, especially in acute cerebral hemorrhage. However, despite several decades of use since it was first synthesized, the clinical utility of centrophenoxine in healthy individuals remains unclear, primarily because the vast majority of published trials test the efficacy of centrophenoxine in treating study populations with specific diseases.

Centrophenoxine is marketed as a general anti-aging supplement, however, we found no evidence in humans to support this purported benefit. Preclinical studies on the effect of centrophenoxine on longevity in animals are also scant. The evidence regarding the use of centrophenoxine as a cognitive enhancer is inconsistent. Many studies employed a wide battery of tests, often reporting a narrow but significant positive result among many assessments that did not change, or occasionally worsened. Most studies were small, less than 30 participants, conducted in older adults with significant cognitive impairment, often in frail clinical condition, and suffered from high dropout rates.

Although low doses are unlikely to cause harm, we conclude that, in the healthy population, the evidence for any benefits of centrophenoxine supplementation is not sufficiently compelling to overcome the precautionary principle.

It is now recognized that T cell functional state in the tumor microenvironment (TME) is a key determinant for effective antitumor immunity and immunotherapy. In addition to exhaustion, cellular senescence in tumor-infiltrating T cells (TILs) has recently been identified as an important T cell dysfunctional state induced by various malignant tumors. Therefore, a better understanding of the molecular mechanism responsible for T cell senescence in the TME and development of novel strategies to prevent effector T cell senescence are urgently needed for cancer immunotherapy.

We report that both mouse malignant tumor cells and regulatory T cells (Tregs) can induce responder T cell senescence, similar as shown in human Treg and tumor cells. Accumulated senescent T cells also exist in the TME in tumor models of lung cancer, breast cancer, and melanoma. Induction of ataxia-telangiectasia mutated protein (ATM)-associated DNA damage is the cause for T cell senescence induced by both mouse tumor cells and Treg cells, which is also regulated by mitogen-activated protein kinase (MAPK) signaling.

Furthermore, blockages of ATM-associated DNA damage and/or MAPK signaling pathways in T cells can prevent T cell senescence mediated by tumor cells and Treg cells in vitro and enhance antitumor immunity and immunotherapy in vivo in adoptive transfer T cell therapy melanoma models. Importantly, prevention of tumor-specific T cell senescence via ATM and/or MAPK signaling inhibition combined with anti-PD-L1 checkpoint blockade can synergistically enhance antitumor immunity and immunotherapy in vivo.

The goals of aging biology research are broad and ambitious - to understand how a multitude of genes, pathways, and mechanisms at multiple scales contribute to declines in function, health and lifespan in ways that can vary across populations, environments and species. Enormous progress has been made identifying individual genes, pathways, molecules and their connection in mechanisms that modulate aging. However, there has been limited progress in our understanding of how these factors interact to produce a global set of aging processes, or in how these processes combine to produce functional phenotypes of aging such as frailty, or demographic patterns such as the Gompertz mortality curves found across the tree of life.

Accordingly, research is increasingly focusing on understanding how mechanisms and pathways integrate, drawing on concepts of complex systems such as resilience, homeostasis, networks, and interactions. This transition to a complex systems view of aging has been happening piecemeal and is only sometimes explicitly acknowledged; many of the core concepts and methods are unfamiliar to biologists and may be defined in various ways. Here, we provide a theoretical framework and introduction to the key concepts of complex systems theory as applied to aging, as a primer to orient researchers new to the field and in the attempt to offer a unifying vision for how a complex systems approach could be transformative in aging biology research.

Researchers initially aimed to recruit 500 cognitively healthy centenarians. As of June 2021, 406 had signed up. Their average age when they joined was 101; the oldest is now 107. Seventy percent are women; 43 percent still live independently. About 30 percent have agreed to donate their brains after death and, to date, 95 of them have passed away. Researchers have presented the neuropathology findings from 85 of those.

At autopsy, some of these centenarians were found to have had pathologies typical of people with Alzheimer's disease (AD). Many had been in stage 2 or 3 amyloidosis when they died, as judged by NIA criteria, and had accumulated stage 2 or even stage 3 neuritic plaques per CERAD scores. All were in at least Braak stage I for neurofibrillary tangles, though the majority were at stage III or higher. The brains weighed about as much as those from people who had had AD dementia, but neither plaques nor tangles correlated with cognitive assessments.

The same was true for a host of other age-related pathologies, including cerebral amyloid angiopathy, TDP-43 proteinopathy, Lewy bodies, hippocampal sclerosis, granulovacuolar degeneration, atherosclerosis, and vascular infarcts. Many centenarians had at least one of these. Across all of these pathologies, increased levels in the postmortem brain generally came with lower cognitive scores before death, but the associations were weak. Of all neuropathological substrates tested, tangles correlated most robustly with lower performance, but these healthy centenarians seemed surprisingly resistant even to the effects of high levels of tangles.

Scientists compared the centenarians' proteomes to those from 50- to 95-year-old people with AD and to 50- to 90-year-old healthy controls. They found that, while concentrations of about two dozen proteins fall with age, in centenarians, these protein levels were higher than expected for their age. For four other proteins that normally tick up with age, levels remained steady in the centenarians. The proteins that bucked these trends included those involved in microtubule and intermediate filament biology, myelination, the immune system, basic metabolism, and protein transport. "In a nutshell, these centenarians have younger-looking brains."

Allostatic load attempts to quantify physiological stress by measuring biomarkers across cardiovascular, immune, and metabolic systems. It has been defined using varying configurations, although most incorporate biomarker measures from these three different categories of physiologic functioning. While there is no consensus definition, we elected to define allostatic load using components including body mass index (BMI), diastolic blood pressure (DBP), glycohemoglobin (hemoglobin A1c), systolic blood pressure (SBP), total cholesterol, serum triglycerides, serum albumin, serum creatinine, and C-reactive protein (CRP).

Chronic stress activates the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system, causing the release of corticosteroids and catecholamines respectively. Frequent exposure to these compounds have been linked to the development of cancer by DNA damage, inhibition of p53, and promoting a microenvironment favoring tumorigenesis. Chronic stress has also been shown to modulate the immune system in favor of conditions for cancer progression. In the innate immune system chronic stress and associated hormones increase pro-inflammatory cytokines. Long term pro-inflammation can influence all stages of cancer development through manipulation of tumor microenvironment, genetic mutation, and epigenetic modifications.

In fully adjusted models, high allostatic load was associated with a 14% increased risk of cancer death among all participants and a 18% increased risk of cancer death among Non-Hispanic White (NH-White) adults. When further stratified by age (participants aged less than 40 years), high allostatic load was associated with a 80% increased risk among all participants; a 95% increased risk among NH-White adults; a 2-fold increased risk among Non-Hispanic Black (NH-Black) adults; and a 36% increased risk among Hispanic adults.