Cancer survivors suffer from progressive frailty, multimorbidity, and premature morbidity. We hypothesize that therapy-induced senescence and senescence progression via bystander effects is a significant cause 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 sub-lethally 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 one year.

Treatments commencing within a month after irradiation effectively reduced frailty progression and improved muscle and liver function as well as short-term memory 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 and short-term memory. 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 non-mitochondrial ROS production via NOX4 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 interventions.

Mitochondria play a critical role in neuron viability or death as it regulates energy metabolism and cell death pathways. They are essential for cellular energy metabolism, reactive oxygen species production, apoptosis, Ca++ homeostasis, aging, and regeneration. Mitophagy and mitochondrial dynamics are thus essential processes in the quality control of mitochondria. According to several recent articles, a continual fusion and fission balance of mitochondria is vital in their normal function maintenance. As a result, the shape and function of mitochondria are inextricably linked. This study examines evidence suggesting that mitochondrial dysfunction plays a significant early impact on AD pathology.

Although mitochondrial dysfunction is a typical indication of Alzheimer's disease, it is unclear whether the cellular systems that maintain mitochondrial integrity malfunction, aggravating mitochondrial pathology. Different levels of vigilance and preventive methods are used to reduce mitochondrial damage and efficiently destroy faulty mitochondria to maintain the mitochondrial equilibrium. The form and function of mitochondria are regulated by mitochondrial fusion and fission. In contrast, mitochondrial transit holds mitochondrial dispersion and transports old and damaged mitochondria from distant axons and synapses to the central cell for lysosomal destruction. As the fundamental mechanisms of mitochondrial quality control, several critical properties of mitochondria work in tandem with mitophagy. According to the findings, mitochondrial viability and function are managed by mitochondrial fusion, fission, transport, and mitophagy, forming a complex, dynamic, and reciprocal interaction network.

According to growing evidence, AD brains have disrupted mitochondrial dynamics and aberrant mitophagy, which may interfere with mitochondrial quality control directly or indirectly. Further research into these processes might help us better understand mitochondrial malfunction in Alzheimer's disease. Given the ability to improve some phenotypes by manipulating genes that regulate mitophagy, there is reason to believe that attempting to subvert mitochondrial dynamics, motility unilaterally, and mitophagy will enhance mitochondrial surveillance mechanisms and decrease the neuropathology of Alzheimer's disease, feasibly leading to new treatment strategies.

Scientists have demonstrated that normal brain aging is accelerated by approximately 26% in people with progressive type 2 diabetes compared with individuals without the disease. The results further suggest that by the time type 2 diabetes is formally diagnosed, there may already be significant structural damage to the brain. There is already strong evidence linking type 2 diabetes with cognitive decline, yet few patients currently undergo a comprehensive cognitive assessment as part of their clinical care. It can be difficult to distinguish between normal brain aging that begins in middle age, and brain aging caused or accelerated by diabetes.

The team made use of the largest available brain structure and function dataset across human lifespan: UK Biobank data from 20,000 people aged 50 to 80 years old. This dataset includes brain scans and brain function measurements and holds data for both healthy individuals and those with a type 2 diabetes diagnosis. They used this to determine which brain and cognitive changes are specific to diabetes, rather than just aging, and then confirmed these results by comparing them with a meta-analysis of nearly 100 other studies.

We characterized neurocognitive effects independently associated with T2DM and age in a large cohort of human subjects from the UK Biobank with cross-sectional neuroimaging and cognitive data. We then proceeded to evaluate the extent of overlap between the effects related to T2DM and age by applying correlation measures to the separately characterized neurocognitive changes. Our findings were complemented by meta-analyses of published reports with cognitive or neuroimaging measures for T2DM and healthy controls (HCs).

T2DM was associated with marked cognitive deficits, particularly in executive functioning and processing speed. Likewise, we found that the diagnosis of T2DM was significantly associated with gray matter atrophy. The structural and functional changes associated with T2DM show marked overlap with the effects correlating with age but appear earlier, with disease duration linked to more severe neurodegeneration. The neurocognitive impact of T2DM suggests marked acceleration of normal brain aging. T2DM gray matter atrophy occurred approximately 26% ± 14% faster than seen with normal aging.

The excitement following the development of epigenetic clocks has been tinged with uncertainty as to the meaning of their measurements (i.e., epigenetic age, EpiAge). This uncertainty is compounded by the fact that different epigenetic clocks appear to measure different features of aging. Our investigations using the Skin&blood clock uncovered many features of epigenetic aging, of which two are particularly important. First, epigenetic aging initiates at very early point of life when pluripotency ceases. This process evidently continues through development, postnatal growth, maturity, and adulthood until death, as epigenetic clocks are applicable to the entire lifespan. Therefore, epigenetic aging is not an auxiliary phenomenon but an integral part of the deterministic process of life. Despite this fact, epigenetic aging is not refractive to the influence of external factors that can alter its rate. Indeed, experiments demonstrate the malleability of the rate of epigenetic aging.

At a higher level of consideration, the innate nature and inevitability of epigenetic aging contrasts with the stochasticity of wear and tear, which is presumed to exert a measurable aging effect only later in life when damage outstrips repair. This, however, does not argue against the relevance of wear and tear and cellular senescence. Instead, these distinct stochastic processes are likely to synergize with epigenetic aging in manifesting the overall phenotypical features of aging. If a successful strategy against aging is to be found, then these distinct and parallel aging mechanisms must be addressed; for example, by the removal of senescent cells, together with the retardation of epigenetic aging.

Another pivotal point concerns the ticking of the clock. It is intuitive to assume that this ticking is owed to dynamic changes of methylation on age-related CpGs in all cells in a tissue. Our observations with cell clones suggest that the ticking of the epigenetic clock is, at the very least, a measure of change in cell composition with age. This change can perceivably occur through expansion or reduction of a subpopulation of cells with different ages within the tissue. It was previously shown that mouse muscle stem cells are considerably younger. Therefore, such changes can conceivably result from alterations in the relative amounts of stem cells and non-stem cells, although the impact of stem cells from many more different tissues to aging requires further empirical investigations.

It was particularly important to address the question of the relationship between epigenetic aging and cellular senescence, as previous reports were equivocal in their conclusions. Here, using primary cells from many individual donors, the results are clear that cellular senescence, although undoubtedly a major contributor to the aging phenotype, is not associated with epigenetic aging, as measured by the Skin&blood clock. Similarly, DNA damage, and genomic instability have been hypothesized and proffered as means by which cells undergo epigenetic aging. Here, using different primary cell types derived from multiple donors, irradiated in different ways (acute or continuous) at different doses and dose rates, we did not observe any measurable impact on the rate of epigenetic aging.

Collectively, the results described here with primary cells from a large number of donors and multiple cell types, as well as in vivo mouse experiments previously reported, indicate that nutrient sensing, mitochondrial function, stem cell exhaustion, and altered cell-cell communication affect epigenetic aging as measured by Skin&blood clock, but cellular senescence, telomere attrition, and genomic instability do not. The connection of epigenetic aging to four of the hallmarks of aging implies that these hallmarks are also mutually connected at a deeper level. If so, epigenetic clocks will be instrumental in identifying the underlying unifying mechanisms. The absence of a connection between the other aging hallmarks and epigenetic aging suggests that aging is a consequence of multiparallel mechanisms, crudely divided into deterministic pathways: those associated with epigenetic aging and stochastic ones, which are independent of epigenetic aging and may result instead from wear and tear.

Analysis of brain protein levels in physiologically aged brain has revealed only minor alterations in protein abundances in the aged adult versus the young adult brain, reflecting differences in inflammation-related proteins or changes in proteasome and ribosome stoichiometry. This indicates that protein turnover, which regulates the equilibrium between protein synthesis and degradation, might be especially affected in aging and could lead to changes preluding neuropathology. Protein synthesis has been historically described as declining with age, although not all studies agree and often point to high organ and tissue variability. Protein degradation is also commonly described as compromised in aging. If both synthesis and degradation decline, lifetimes should increase and general turnover of proteins should be slower, possibly favoring the collapse of proteostasis networks and initiating the accumulation of potentially toxic proteins. While this general trend would explain the malfunctioning of macromolecules, protein turnover in different tissues has shown little or no overall changes in aged animals versus younger controls.

While results in invertebrate models suggest that proteostasis is essential for the survival of aging neurons, and that there is an age-related decline in protein turnover rates, in the aged mammalian brain an extensive quantitative analysis of protein turnover is currently lacking. Our group has introduced an experimental workflow for the global quantification of protein lifetimes. Here, using this workflow, we obtained protein lifetimes in the aged brain cortex, in cerebellum, and in their synaptic fractions, aiming to provide cellular and subcellular information about changes in brain protein stability. We then compared protein lifetimes between young adult and aged mice addressing the changes observed during aging. We analyzed our results extensively with bioinformatics and revealed that the proteome in the aged brain is turned over at a slower rate (~20%). In addition, aging establishes an intrinsic alteration of the proteostasis network that specifically preserves proteins with high biosynthetic cost.

Neurodegeneration is a pathological condition in which nervous system or neuron losses its structure, function, or both leading to progressive neural degeneration. Growing evidence strongly suggests that reduction of plasmalogens (Pls), one of the key brain lipids, might be associated with multiple neurodegenerative diseases, including Alzheimer's disease (AD). Plasmalogens are abundant members of ether-phospholipids. Approximately 1 in 5 phospholipids are plasmalogens in human tissue where they are particularly enriched in brain, heart and immune cells.

In this study, we employed a scheme of 2-months Pls intragastric administration to aged female C57BL/6J mice, starting at the age of 16 months old. Noticeably, the aged Pls-fed mice exhibited a better cognitive performance, thicker and glossier body hair in appearance than that of aged control mice. The transmission electron microscopic (TEM) data showed that 2-months Pls supplementation surprisingly alleviates age-associated hippocampal synaptic loss and also promote synaptogenesis and synaptic vesicles formation in aged murine brain. Further analyses confirmed that plasmalogens remarkably enhanced both the synaptic plasticity and neurogenesis in aged murine hippocampus. In addition, we have demonstrated that Pls treatment inhibited the age-related microglia activation and attenuated the neuroinflammation in the murine brain.

These findings suggest for the first time that Pls administration might be a potential intervention strategy for halting neurodegeneration and promoting neuroregeneration.

In patients with age-related macular degeneration (AMD), the crucial retinal pigment epithelial (RPE) cells are characterized by mitochondria that are structurally and functionally defective. Moreover, deficient expression of the mRNA-editing enzyme Dicer is noted specifically in these cells. This Dicer deficit up-regulates expressionttps://en.wikipedia.org/wiki/Gene_expression">expression of Alu RNA, which in turn damages mitochondria - inducing the loss of membrane potential, boosting oxidant generation, and causing mitochondrial DNA to translocate to the cytoplasmic region. The cytoplasmic mtDNA, in conjunction with induced oxidative stress, triggers a non-canonical pathway of NLRP3 inflammasome activation, leading to the production of interleukin-18 that acts in an autocrine manner to induce apoptotic death of RPE cells, thereby driving progression of dry AMD.

It is proposed that measures which jointly up-regulate mitophagy and mitochondrial biogenesis (MB), by replacing damaged mitochondria with "healthy" new ones, may lessen the adverse impact of Alu RNA on RPE cells, enabling the prevention or control of dry AMD. An analysis of the molecular biology underlying mitophagy/MB and inflammasome activation suggests that nutraceuticals or drugs that can activate Sirt1, AMPK, Nrf2, and PPARα may be useful in this regard. These include ferulic acid, melatonin, urolithin A, and glucosamine (Sirt1), metformin and berberine (AMPK), lipoic acid and broccoli sprout extract (Nrf2), and fibrate drugs and astaxanthin (PPARα). Hence, nutraceutical regimens that provide physiologically meaningful doses of several or all of the above may have potential for control of dry AMD.

A new study found a gene called FMNL2 links cerebrovascular disease and Alzheimer's and suggests changes in FMNL2 activity caused by cerebrovascular disease prevent the efficient clearance of toxic proteins from the brain, eventually leading to Alzheimer's disease. Researchers found FMNL2 in a genome-wide hunt designed to uncover genes associated with both vascular risk factors and Alzheimer's disease. The search involved five groups of patients representing different ethnic groups.

The blood-brain barrier is a semi-permeable, highly controlled border between capillaries and brain tissue that serves as a defense against disease-causing pathogens and toxins in the blood. Astrocytes, a specialized type of brain cell, compose and maintain the structure of the blood-brain barrier by forming a protective sheath around the blood vessel. This astrocyte sheath needs to loosen for the clearance of toxic amyloid - the aggregates of proteins that accumulate in the brain and lead to Alzheimer's disease.

A zebrafish model confirmed the presence of FMNL2 in the astrocyte sheath, which retracted its grip on the blood vessel once toxic proteins were injected into the brain, presumably to allow for clearance. When researchers blocked the function of FMNL2, this retraction did not occur, preventing clearance of amyloid from the brain. The same process was then confirmed using transgenic mice with Alzheimer's disease.

The same process may also occur in the human brain. The researchers studied postmortem human brains and found increased expression of FMNL2 in people with Alzheimer's disease, along with breach of the blood-brain barrier and retraction of the astrocytes. Based on these findings, the researchers propose that FMNL2 opens the blood-brain-barrier - by controlling its astrocytes - and promotes the clearance of extracellular aggregates from the brain. And that cerebrovascular disease, by interacting with FMNL2, reduces the clearance of amyloid in the brain.

The rate of aging and lifespan regulation depend on genetic and non-genetic or environmental factors. A significant amount of data has now established that the environment has a profound effect on lifespan regulation, with diet and stress being predominant factors determining survival, at the cellular, tissue, and organismal levels. Cells perceive nutrients, i.e., amino acids and sugars, through nutrient-responsive pathways that are hard-wired to basic metabolic processes, such as gene transcription, protein translation, proteostasis, and protein degradation rates, mitochondrial function, such as detoxification and respiration, as well as autophagy.

In this review, we provide a framework of knowledge about the role of nutrient-responsive pathways in lifespan and healthspan regulation, such as the Insulin Growth Factor (IGF) and mechanistic Target of Rapamycin (mTOR), and an update on the advancements in this scientific field. We briefly refer to fundamental principles of these pathways. In summary, activation of the related signaling controlled by IGF and mTOR, while beneficial early in life, supporting growth and development, seems detrimental in lifespan and healthspan. While the fundamental molecular players around these pathways - although not fully characterized - are sketched on a satisfactory level within simpler organisms, such as yeasts, D. melanogaster, and C. elegans, additional studies are needed to understand functional links on a genome-wide scale. Moreover, single or combinatorial drug treatments that target specific nutrient-responsive and other signaling pathways that affect growth, have been utilized to test effects on lifespan, as well as in healthspan, such as, amelioration of pathological states that might phenocopy age-related diseases or syndromes.

Nevertheless, genetics, as well as epigenetics, of human aging and the role of diet on human lifespan regulation are still being worked out. The field is utilizing stem cell technologies, patient samples, and organoids to bridge this gap and has found itself mature enough to proceed to large studies and clinical trials using mammalian species close to humans, such as dogs. However, cross-species comparisons reveal differential tempos, not only in differentiation programs but also within fundamental processes, such as proteostasis and protein half-life patterns, that can affect aging processes and lifespan and healthspan. These studies show that the precise, quantitative outcomes in model organisms might differ from conditions in the human body or even in human cohorts. Therefore, although the contribution of model organisms in biogerontology studies is significant in understanding underlying molecular mechanisms, interdisciplinary studies combining genetics, biomarker analyses, diet and drug surveys, and interventions in human populations are now needed within the field.

Mild impairment of mitochondrial function has been shown to increase lifespan in genetic model organisms including worms, flies and mice. To better understand the mechanisms involved, we analyzed RNA sequencing data and found that genes involved in the mitochondrial thioredoxin system, trx-2 and trxr-2, are specifically upregulated in long-lived mitochondrial mutants but not other non-mitochondrial, long-lived mutants. Upregulation of trx-2 and trxr-2 is mediated by activation of the mitochondrial unfolded protein response (mitoUPR). While we decided to focus on the genes of the mitochondrial thioredoxin system for this paper, we identified multiple other antioxidant genes that are upregulated by the mitoUPR in the long-lived mitochondrial mutants including sod-3, prdx-3, gpx-6, gpx-7, gpx-8, and glrx-5.

In exploring the role of the mitochondrial thioredoxin system in the long-lived mitochondrial mutants, nuo-6 and isp-1, we found that disruption of either trx-2 or trxr-2 significantly decreases their long lifespan, but has no effect on wild-type lifespan, indicating that the mitochondrial thioredoxin system is specifically required for their longevity. In contrast, disruption of the cytoplasmic thioredoxin gene trx-1 decreases lifespan in nuo-6, isp-1, and wild-type worms, indicating a non-specific detrimental effect on longevity. Disruption of trx-2 or trxr-2 also decreases the enhanced resistance to stress in nuo-6 and isp-1 worms, indicating a role for the mitochondrial thioredoxin system in protecting against exogenous stressors. Overall, this work demonstrates an important role for the mitochondrial thioredoxin system in both stress resistance and lifespan resulting from mild impairment of mitochondrial function.

Therapeutic strategies such as lifestyle modifications (weight loss and increased physical activity), antihypertensive therapy, and lipid-lowering medications have shown variable effectiveness at improving endothelial function and ameliorating arterial stiffening and remodeling in older adults. Thus, additional therapeutic approaches aimed at improving vascular health in older individuals are needed. In this regard, evidence from different clinical trials demonstrates that inhibition of SGLT2 results in decreased cardiovascular events and cardiovascular disease related mortality in both patients with and without diabetes. SGLT2 co-transporters are predominantly located in the proximal renal tubules and are responsible for reabsorption of 90% of the glucose in the glomerular filtrate. Indeed, while SGLT2 inhibitors were originally designed as glucose lowering agents, growing evidence supports their beneficial, non-glucose lowering dependent, renal, and cardiovascular effects. In particular, the SGLT2 inhibitor empagliflozin (Empa) has been shown to reduce cardiovascular mortality and nonfatal myocardial infarction, stroke, and cardiovascular death regardless of the presence of type 2 diabetes.

Mechanisms postulated to explain the beneficial cardiovascular properties of SGLT2 inhibition include weight loss and antihypertensive effect, diuresis-induced blood volume reduction, increased red blood cell mass, improved myocardial bioenergetics, decreased arterial stiffness, and improved endothelial function. However, the extent to which the favorable cardiovascular effects of SGLT2 inhibitors are translatable to aging remains unknown. Given the above, the potential impact of SGLT2 inhibition on aging-related endothelial dysfunction, arterial stiffening, and remodeling warrants investigation.

Herein, we first confirmed in a cohort of adult human subjects that aging is associated with impaired endothelial function and increased arterial stiffness and that these two variables are inversely correlated. Next, we investigated whether treatment with the SGLT2 inhibitor, Empa, for 6 weeks ameliorates endothelial dysfunction and reduces arterial stiffness in aged mice with confirmed vascular dysfunction. We report that Empa-treated mice exhibit an improvement in mesenteric endothelial function when compared with control, in parallel with reduced mesenteric artery and aortic stiffness. Our findings demonstrate that Empa improves endothelial function and reduces arterial stiffness in a preclinical model of aging, making SGLT2 inhibition a potential therapeutic alternative to reduce the progression of cardiovascular disease in older individuals.

Researchers have demonstrated that diffusion-weighted MRI (dw-MRI) can noninvasively and differentially detect the activation of microglia and astrocytes, two types of brain cells that are at the basis of neuroinflammation and its progression. Degenerative brain diseases such as Alzheimer's and other dementias, Parkinson's, or multiple sclerosis are a pressing and difficult problem to address. Sustained activation of two types of brain cells, microglia and astrocytes leads to chronic inflammation in the brain that is one of the causes of neurodegeneration and contributes to its progression.

This is the first time it has been shown that the signal from this type of MRI can detect microglial and astrocyte activation, with specific footprints for each cell population. The researchers have also shown that this technique is sensitive and specific for detecting inflammation with and without neurodegeneration, so that both conditions can be differentiated. In addition, it makes it possible to discriminate between inflammation and demyelination characteristic of multiple sclerosis.

To validate the model, the researchers used an established paradigm of inflammation in rats based on intracerebral administration of lipopolysaccharide (LPS). In this paradigm, neuronal viability and morphology are preserved, while inducing, first, an activation of microglia, and in a delayed manner, an astrocyte response. This temporal sequence of cellular events allows glial responses to be transiently dissociated from neuronal degeneration and the signature of reactive microglia investigated independently of astrogliosis. To isolate the imprint of astrocyte activation, the researchers repeated the experiment by pretreating the animals with an inhibitor that temporarily ablates about 90% of microglia.

Converging evidence from both genetically at-risk cohorts and clinically normal older individuals suggests that the pathogenesis of Alzheimer's disease (AD) begins years before the clinical diagnosis of dementia is established. Over time, the definition of AD has changed from a traditionally symptom-based disease entity to a clinico-biological construct encompassing a 15-20 year preclinical phase, a 3-6 year prodromal period and a terminal dementia stage.

In addition to deposition of extracellular amyloid-β plaques and intracellular neurofibrillary tangles, neuroinflammation has been identified as the third core characteristic crucial in the pathogenesis of AD. Accumulating evidence suggests that neuroinflammation, as well as activation of microglia and astrocytes, plays an important role in AD pathogenesis. Although whether or not inflammation itself is an initiator or consequence of the disease process, its importance in AD is undeniable.

Targeting of neuroinflammation is potentially an extremely effective strategy for AD prevention and therapy during the preclinical stage prior to the occurrence of significant neuronal loss. Several phase I/II clinical trials evaluating the targeting of TNF-α, TREM2, or CD33 have shown promising results. As reported data remain controversial, and most of the AD clinical trials - including those investigating anti-inflammatory compounds - failed, longitudinal studies enrolling large cohorts of participants with accurate clinical and biomarker-based characterizations are needed to identify potentially effective anti-inflammatory targets and drugs relevant to AD therapy.

A sustained state of methionine restriction (MR) dramatically extends the healthspan of several model organisms. For example, continuously methionine-restricted rodents have less age-related pathology and are up to 45% longer-lived than controls. Promisingly, MR is feasible for humans, and studies have suggested that methionine-restricted individuals may receive similar benefits to rodents. However, long-term adherence to a methionine-restricted diet is likely to be challenging for many individuals. Prompted by this, and the fact that intermittent variants of other healthspan-extending interventions (i.e., intermittent fasting and the cyclic ketogenic diet) are just as effective, if not more, than their continuous counterparts, we hypothesized that an intermittent form of MR might produce similar healthspan benefits to continuous MR.

Accordingly, we developed two increasingly stringent forms of intermittent MR (IMR) and assessed whether mice maintained on these diets demonstrate the beneficial metabolic changes typically observed for continuous MR. To the best of our knowledge, we show for the first time that IMR produces similar beneficial metabolic effects to continuous MR, including improved glucose homeostasis and protection against diet-induced obesity and hepatosteatosis. In addition, like continuous MR, IMR confers beneficial changes in the plasma levels of the hormones IGF-1, FGF-21, leptin, and adiponectin. Together, our findings demonstrate that the more practicable intermittent form of MR produces similar healthspan benefits to continuous MR, and thus may represent a more appealing alternative to the classical intervention.

A further consequence of population ageing is the increase in multimorbidity, conventionally defined as the presence of two or more chronic diseases irrespective of the severity of such conditions. Recent estimates suggest that more than 50% of older adults in high income countries report multiple chronic conditions, although multimorbidity is not confined to older adults. The development of chronic diseases at younger ages has implications for their management, the risk of premature mortality, and the cost of care. Multimorbidity is estimated to have an adverse effect on patients' outcomes and healthcare systems that is greater than that of chronic conditions considered indivdually.

In older adults with dementia, the presence of several comorbid conditions is common. A recent study of older adults (mean age 75 years) followed for a mean of 8.4 years reported higher risk of dementia in those with multimorbidity, but studies that have followed individuals for longer are lacking. Recent studies also suggest that the risk of dementia is higher in people with cardiometabolic disease in midlife rather than late life, suggesting that age at onset of multimorbidity is an important determinant of risk of dementia.

Accordingly, we examined whether longer duration of multimorbidity and severity of multimorbidity (defined as three or more chronic conditions), implying earlier age at onset of multimorbidity, increase the risk of dementia at older ages in the Whitehall II cohort study spanning 30 years. The prevalence of multimorbidity (≥2 chronic diseases) was 6.6% (655/9937) at age 55 and 31.7% (2464/7783) at age 70; 639 cases of incident dementia occurred over a median follow-up of 31.7 years. After adjustment for sociodemographic factors and health behaviours, multimorbidity at age 55 was associated with subsequent risk of dementia, hazard ratio 2.44. Multimorbidity, particularly when onset is in midlife rather than late life, has a robust association with subsequent dementia. The increasingly younger age at onset of multimorbidity makes prevention of multimorbidity in people with a first chronic disease important.