Fight Aging! Newsletter, August 2nd 2021

A striking feature of cellular senescence is a stable cell cycle arrest, which prohibit the replication of damaged cells and consequently limit the tissue damage and resist tumorigenesis in the short-term. However, senescent cells become harmful in the long term, especially through secreting soluble factors including cytokines, chemokines, and matrix proteases, called senescence-associated secretory phenotype (SASP). Eliminating senescent cells prevents age-related organ dysfunction in the heart and kidney, and notably, expands the lifespan in mice. Also, senescent cell-depletion and senolytic agents that preferentially kill senescent cells improved physical function and showed beneficial effects in age-related diseases such as osteoarthritis and atherosclerosis. These findings strongly suggest the critical and causative role of cellular senescence in age-related diseases.

Senescence of vascular cells is involved in age-related vascular dysfunction including atherosclerosis. Senescent vascular cells have been detected in atherosclerotic plaque, and eliminating senescent cells prevented the progression of atherosclerosis. Also, crucial and causative roles of vascular smooth muscle cell senescence in atherosclerosis have been reported. However, a role of endothelial cell (EC) senescence in atherogenesis remains to be elusive, though potential role of senescent EC in atherosclerosis was reported. By utilizing endothelial progeroid mice, we identified EC senescence promotes atherosclerosis potentially through EC hyper-inflammability due to epigenetic alteration.

Bone marrow mesenchymal stem cells (BMSCs) are a population of multipotent progenitor cells that have regenerative potential of various tissues. With aging, the function of BMSCs declines dramatically, and limited interventions exist to rejuvenate BMSC population from aged donors. The underlying mechanisms of age-related changes in BMSCs are not fully characterized. With aging, a portion of BMSCs might become senescent like other MSCs, and contribute to these changes. Cellular senescence refers to the stable arrest of cellular proliferation, and might impact aged BMSCs function by both intrinsic and extrinsic mechanisms.

Recently, various senolytic drugs have been developed to specifically kill senescent cells. The cocktail of dasatinib and quercetin (D + Q) is the first reported senolytic agents, and eliminates senescent cells by transiently suppressing senescence-associated anti-apoptotic pathways which are highly activated in senescent cells. In this study, an in vitro cell culture and in vivo transplantation model was used to assess the effect of D + Q on inherent osteogenic potential of BMSCs derived from old donors.

BMSCs cultures were established from young (3 month-old) and old (27 month-old) male mice, and were treated with vehicle (V) or D + Q for 24 hours. At the end of the 24 hour treatment period, an ATP-based assay revealed that D + Q-treated old BMSC cultures had 20-30% lower cell number than V-treated cells while the reduction of cell number in young BMSCs by D + Q was only 10%. These results indicate that D + Q has age-preferential killing effects on certain cell populations in BMSCs. The cultures were stained with senescence associated beta-galactosidase (SABG), a classic biomarker for cellular senescence in vitro. Old BMSCs contained more SABG + cells (20%) than young BMSCs (10%) and D + Q reduced SABG + cells in old (10%) but not young BMSCs.

The effect of D + Q on the bone forming potential of old BMSCs in vivo was assessed using the calvarial defect model. D + Q- or V-treated old BMSCs as well as young BMSC cultures were loaded into collagen-hydroxyapatite (HA) scaffolds and implanted into calvarial defects in 3-month-old immunodeficient mice. The area of newly formed mineralized tissue relative to the defect size was significantly lower in calvaria transplanted with V-treated old BMSCs (50%) compared to both young (90%) and D + Q-treated old cells (80%).

In summary, D + Q treatment improved the osteogenic capacity of old BMSCs, and resulted in bone organoids with restored bone remodeling and an enlarged and functional bone marrow space. D + Q does appear to be beneficial for restoring the bone and bone marrow forming potential of old BMSCs. These agents along with other senolytic compounds hold promise for improving BMSC function in aged populations.

Transcranial direct current stimulation (tDCS) is a non-invasive tool for neuromodulation that has proven to be well-tolerated and safe. This technique employs low-intensity continuous or galvanic current applied transcutaneously via electrodes placed on the scalp. The change generated in the electric potential of the membrane of the underlying neurons affects neuronal excitability, which varies depending on the orientation of the electric field determined by the position and polarity of the electrodes. This effect on excitability is believed to be related to transient changes in the synaptic efficiency of different neurotransmitters.

Complex structural and functional changes in the brain are some of the processes related to normal aging that entail deterioration of cognitive, perception, and motor capacities, which affects daily life activities, independence, and quality of life. The main finding observed is the increase in dual-task costs, and the most affected ability due to aging is the simultaneous execution of one motor and one cognitive task. Additionally, older adults present a reduction in the structural and functional plasticity of the brain and in flexibility for tasks requiring previous learning. Trials using neuroimaging indicate that the left dorsolateral prefrontal cortex (DLPFC), which intervenes in the executing function, is one of the key brain regions involved in performing combined cognitive and motor tasks under dual-task conditions. For this reason, tDCS interventions designed for facilitating the functional activation of the DLPFC and its neuronal networks could improve the cognitive function and motor performance in the elderly.

This systematic review aimed at compiling and summarizing the currently available scientific evidence about the effect of tDCS on functionality in older adults over 60 years of age. A search of databases was conducted to find randomized clinical trials that applied tDCS versus sham stimulation in the above-mentioned population. No limits were established in terms of date of publication. A total of 237 trials were found, of which 24 met the inclusion criteria. Finally, nine studies were analyzed, including 260 healthy subjects with average age between 61.0 and 85.8 years. Seven of the nine included studies reported superior improvements in functionality variables following the application of tDCS compared to sham stimulation. Anodal tDCS applied over the motor cortex may be an effective technique for improving balance and posture control in healthy older adults. However, further high-quality randomized controlled trials are required to determine the most effective protocols and to clarify potential benefits for older adults.

The accumulation of misfolded protein aggregates in affected brain regions is a common hallmark shared by several neurodegenerative diseases (NDs). Mounting evidence in cellular and in animal models highlights the capability of different misfolded proteins to be transmitted and to induce the aggregation of their endogenous counterparts, this process is called "seeding". In Parkinson's disease, the second most common ND, misfolded α-synuclein (α-syn) proteins accumulate in fibrillar aggregates within neurons. Those accumulations are named Lewy bodies.

In 2016, a team of researchers demonstrated that α- syn fibrils spread from donor to acceptor cells through tunneling nanotubes (TNTs). They also found out that these fibrils are transferred through TNTs inside lysosomes. Following this original discovery, researchers now shed some light on how lysosomes participate in the spreading of α-syn aggregates through TNTs. "By using super-resolution and electron microscopy, we found that α-syn fibrils affect the morphology of lysosomes and impair their function in neuronal cells. We demonstrated for the first time that α-syn fibrils induce the peripheral redistribution of the lysosomes thus increasing the efficiency of α-syn fibrils' transfer to neighbouring cells."

They also showed that α-syn fibrils can permeabilize the lysosomal membrane, impairing the degradative function of lysosomes and allowing the seeding of soluble α-syn, which occurs mainly in those lysosomes. Thus, by impairing lysosomal function α-syn fibrils block their own degradation in lysosomes, that instead become a hub for the propagation of the pathology.

The accumulation of α-synuclein (α-syn) aggregates in specific brain regions is a hallmark of synucleinopathies including Parkinson disease (PD). α-Syn aggregates propagate in a "prion-like" manner and can be transferred inside lysosomes to recipient cells through tunneling nanotubes (TNTs). However, how lysosomes participate in the spreading of α-syn aggregates is unclear. Here, by using super-resolution (SR) and electron microscopy (EM), we find that α-syn fibrils affect the morphology of lysosomes and impair their function in neuronal cells. In addition, we demonstrate that α-syn fibrils induce peripheral redistribution of lysosomes, likely mediated by transcription factor EB (TFEB), increasing the efficiency of α-syn fibrils' transfer to neighboring cells.

We also show that lysosomal membrane permeabilization (LMP) allows the seeding of soluble α-syn in cells that have taken up α-syn fibrils from the culture medium, and, more importantly, in healthy cells in coculture, following lysosome-mediated transfer of the fibrils. Moreover, we demonstrate that seeding occurs mainly at lysosomes in both donor and acceptor cells, after uptake of α-syn fibrils from the medium and following their transfer, respectively. Finally, by using a heterotypic coculture system, we determine the origin and nature of the lysosomes transferred between cells, and we show that donor cells bearing α-syn fibrils transfer damaged lysosomes to acceptor cells, while also receiving healthy lysosomes from them.

These findings thus contribute to the elucidation of the mechanism by which α-syn fibrils spread through TNTs, while also revealing the crucial role of lysosomes, working as a Trojan horse for both seeding and propagation of disease pathology.

Socioeconomic disparities in life expectancy are substantial in size. Financial wealth or net worth, which is the value of an individual's assets (such as savings, real estate, and vehicles) minus liabilities, is directly associated with longevity. However, a challenge in this area of research has been eliminating or minimizing the potential for confounding by the early environment and heritable traits, either of which could simultaneously affect socioeconomic conditions in adulthood and health in the course of life.

Full siblings who were raised in the same family share much of their early rearing environment and are genetically related to one another. Thus, in sibling-comparison studies, factors that are shared between siblings are controlled. Twin comparisons provide an even greater control of family-level early-life confounding and, in the case of monozygotic (MZ) twins, control for all heritable genetic factors. Previous research found that discordance in occupational prestige was associated with cardiovascular risk and overall mortality; twins with lower-prestige jobs had worse health on both outcomes compared with their co-twins with higher-prestige jobs. This pattern suggests that socioeconomic disparities in health are affected by experiential factors in adulthood over and above any potential confounders that involve the siblings' shared early environment and genetic characteristics. In other discordant sibling and twin analyses, educational attainment and composite measures of adult socioeconomic position also have been associated with better adult health outcomes and longevity. However, results from these and other studies that used different methods do suggest these associations may be partially explained by shared family-level environmental factors or genetic predispositions.

Comparatively little attention has been given to wealth disparities, a potentially important oversight. In this cohort study, we used a discordant sibling design to conservatively estimate the association between wealth and longevity. Specifically, we aimed to identify the association between net worth at midlife (the middle years of life) and subsequent all-cause mortality in individuals as well as within siblings and twin pairs. We posed two research questions. First, was wealth accumulation at midlife associated with longevity over a nearly 24-year follow-up? Consistent with previous work, we expected that higher wealth accumulation would be associated with increased longevity. Second, was the wealth-longevity association present over and above controls for family and heritable factors that could confound this association?

In this cohort study of 5,414 participants in the Midlife in the United States study, those who had accumulated a higher net worth by midlife had significantly lower mortality risk over the subsequent 24 years. In sibling and twin comparison models that controlled for shared early life experiences and genetic influence, the association between net worth and longevity was similar in magnitude. Thus net worth at midlife was associated with longevity among adults in the study, and this association is unlikely to be merely an artifact of early experiences or heritable traits shared by families.

The concentration of remarkable-aged individuals, within geographic regions or 'blue zones' or within databases of people exceeding extreme age thresholds, has stimulated diverse efforts to understand factors driving survival patterns in these populations. Populations within remarkable-age databases and 'blue zone' regions have been subject to extensive analysis of lifestyle patterns, social connections, biomarkers, and genomic variants, under the assumption that these represent potential drivers behind the attainment of remarkable age.

However, alternative explanations for the distribution of remarkable age records appear to have been overlooked or downplayed. Previous work has noted the potential of bad data, population illiteracy or population heterogeneity to explain remarkable age patterns. More recent investigations revealed a potential role of errors, and potential operator biases in generating old-age survival patterns and data. In turn, these findings prompted a response with potentially disruptive implications: that, under such models, the majority if not all remarkable age records may be errors.

Here, we explore this possibility by linking civil registration rates and socioeconomic data to per-capita rates of remarkable age attainment, using data from every known centenarian (individuals aged 100 or over), semisupercentenarian (SSCs; aged 105 or over), and supercentenarian (aged 110 or over) from the USA, France, Japan, the United Kingdom, and Italy. These data reveal that remarkable age attainment is predicted by regional indicators of error and fraud including greater poverty, higher illiteracy, higher crime rates, worse population health, greater levels of material deprivation, shorter average lifespans, fewer old people, and the absence of birth certificates. In addition, French and Italian historical data indicate that supercentenarians are not likely to be born into longer-lived cohorts, but are born into undifferentiated or shorter-lived populations relative to their contemporary national averages.

Supercentenarian birthdates also exhibit 'age heaping' distributional patterns that are strongly indicative of manufactured birth data. Finally, fewer than 15% of exhaustively validated supercentenarians are associated with either a birth certificate or a death certificate, even in populations with over 95% death certificate coverage. As such, these findings suggest that extreme age data are largely a result of vital statistics errors and patterns of fraud, raising serious questions about the validity of an extensive body of research based on the remarkable reported ages of populations and individuals.

Biological age is the concept of using biophysiological measures to more accurately determine an individual's age-related risk of adverse outcomes. Grading of the degree of frailty and measuring biomarkers are distinct methods of measuring biological age. Chronological age is rigid and fails to account for the variable effects of time on individuals. The construct of "biological age" aims to give a more ordered relation between an individual's current health state and their proximity to death. This in turn can enable a novel approach to individualizing care and potentially yield ways in which aging might be modified.

A quantitative approach to frailty yields a proxy measure of biological age that can be formulated from deficit accumulation indices and geriatric assessment. The great advantage of this approach is that it offers information that is immediately relevant to guiding treatment strategies and estimating prognosis. Biomarkers derived from the mechanistic underpinnings of aging hold out the promise of measuring processes of aging before clinically recognizable deficits ensue. So doing, they can complement the information about individuals' health that is required for appropriate care planning and that can readily be summarized in a frailty index. These clinically derived frailty indices can outperform measures of biological age in predicting proximity to death without incorporating chronological age into their measurement. Furthermore, the cost of routinely performing sophisticated biomarker-based measures of biological age is prohibitive.

Complementarity of biomarkers and frailty indices can be demonstrated through both measures used simultaneously or by being combined. Further, frailty indices can use biomarkers as deficits, even when normal ranges have not been established for that purpose. In ways like this, the siloed approach to biological biomarkers can be overcome, and perhaps enhanced, through their combination with frailty measures that are likely already to be in the clinical record or that can feasibly be derived from it.

Loss of mitochondrial function contributes to fatigue, exercise intolerance, and muscle weakness, and is a key factor in the disability that develops with age and a wide variety of chronic disorders. Here, we describe the impact of a first-in-class cardiolipin-binding compound that is targeted to mitochondria and improves oxidative phosphorylation capacity (Elamipretide, ELAM) in a randomized, double-blind, placebo-controlled clinical trial.

Non-invasive magnetic resonance and optical spectroscopy provided measures of mitochondrial capacity (ATPmax) with exercise and mitochondrial coupling at rest. The first dorsal interosseous (FDI) muscle was studied in 39 healthy older adult subjects (60 to 85 yrs of age; 46% female) who were enrolled based on the presence of poorly functioning mitochondria. We measured volitional fatigue resistance by force-time integral over repetitive muscle contractions.

A single ELAM dose elevated mitochondrial energetic capacity in vivo relative to placebo immediately after a 2-hour infusion. No difference was found on day 7 after treatment, which is consistent with the half-life of ELAM in human blood. No significant changes were found in resting muscle mitochondrial coupling. Despite the increase in ATPmax there was no significant effect of treatment on fatigue resistance in the FDI.

These results highlight that ELAM rapidly and reversibly elevates mitochondrial capacity after a single dose. This response represents the first demonstration of a pharmacological intervention that can reverse mitochondrial dysfunction in vivo immediately after treatment in aging human muscle.

Researchers have been developing cancer diagnostics that work by generating synthetic biomarkers that can be easily detected in the urine. Most cancer cells express enzymes called proteases, which help them escape their original locations by cutting through proteins of the extracellular matrix. Cancer-detecting nanoparticles are coated with peptides that are cleaved by these proteases. When these particles encounter a tumor, the peptides are cleaved and excreted in the urine, where they can be easily detected. In animal models of lung cancer, these biomarkers can detect the presence of tumors early on; however, they don't reveal the exact location of the tumor or whether the tumor has spread beyond its organ of origin.

Building on their previous efforts,researchers wanted to develop what they call a "multimodal" diagnostic, which can perform both molecular screening (detecting the urinary signal) and imaging, to tell them exactly where the original tumor and any metastases are located. To modify the particles so they could also be used for PET imaging, the researchers added a radioactive tracer. They also coated them with a peptide that is attracted to acidic environments, such as the microenvironment in tumors, to induce the particles to accumulate at tumor sites. Once they reach a tumor, these peptides insert themselves into cell membranes, creating a strong imaging signal above background noise.

The researchers tested the diagnostic particles in two mouse models of metastatic colon cancer, in which tumor cells travel to and grow in the liver or the lungs. After treatment with a chemotherapy drug commonly used to treat colon cancer, the researchers were able to use both the urine signal and the imaging agent to track how the tumors responded to treatment. This kind of diagnostic could be useful for evaluating how well patients respond to treatment, and for long-term monitoring of tumor recurrence or metastasis, especially for colon cancer. In the longer term, researchers hope that this technology could be used as part of a diagnostic workflow that could be given periodically to detect any kind of cancer.

Fighting a tumor is a marathon, not a sprint. For cancer-fighting T cells, the race is sometimes just too long, and the T cells quit fighting. Researchers even have a name for this phenomenon: T cell exhaustion. Researchers now report that T cells can be engineered to clear tumors without succumbing to T cell exhaustion. This research builds on work that has shown the key role of proteins called transcription factors in the cellular pathway that triggers T cell exhaustion. This work is important because T cell exhaustion continues to plague even the most cutting-edge cancer immunotherapies.

With CAR T therapies, for example, researchers take T cells from a cancer patient and "arm" them by altering the expression of genes that aid in the cancer fight. Researchers make more of these special T cells, which then go back into the patient. CAR T therapies are different from immunotherapies, which aim to activate the patient's existing T cell population. With both approaches, T cell exhaustion rears its ugly head. "Many people have tried to use CAR T therapies to kill solid tumors, but it's been impossible because the T cells become exhausted."

The new study addresses this problem by giving T cells the ability to fight exhaustion itself. To accomplish this, the researchers screened T cells to uncover which transcription factors could boost a T cell's "effector" program, an important step in readying T cells to kill cancer cells. This screening process led the researchers to BATF, a transcription factor that they found cooperates with another transcription factor called IRF4 to counter the T cell exhaustion program.

In mouse melanoma and colorectal carcinoma tumor models, altering CAR T cells to also overexpress BATF led to tumor clearance without prompting T cell exhaustion. The CAR T therapy worked against solid tumors. Encouragingly, some altered T cells also stuck around and became memory T cells. This is important because T cell exhaustion often prevents T cells from mounting a strong memory response to recurrent cancers.

Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting ~2% of the population over age 70. Disease prevalence increases with age and, given the aging population, may triple in the next few years. The neurodegenerative mechanism leading to PD is still not completely elucidated. Alpha-synuclein may drive the neurodegenerative process of PD. When aggregated in neurons as intracellular Lewy bodies, it constitutes the pathologic hallmark of PD. On the other hand, mitochondrial dysfunction, oxidative stress, and selective neuronal loss each contribute to PD pathology.

Unfortunately, there remains no disease-modifying treatment in PD despite multiple trials of promising preclinical targets. Supplements and dietary interventions have been periodically considered as possible therapeutic approaches to impact disease progression and severity in related neurodegenerative disorders. One such intervention is intermittent fasting (IF). This viewpoint seeks to describe the putative pathophysiologic relationships among mitochondria, alpha-synuclein, and PD risk genes, and to provide a background for the rationale or the use of IF and similar mitochondrial-targeting therapies in PD. Finally, we propose an outline for determining the efficacy of an IF intervention in PD.

Frailty is a clinical syndrome characterized by "diminished strength, endurance, and reduced physiological function". Frailty predisposes patients to negative health-related outcomes such as falls, hospitalization, disability, dependency, and mortality. The prevalence of frailty ranges from 4% to 59% in community-dwelling older adults and increases with age. Given the rapidly aging population, the United Nations estimates that worldwide, the number of people aged 60 years and above will double to nearly 2.1 billion by 2050. Therefore, frailty is a pressing concern in aging societies.

Microorganisms, as an environmental factor, are among the most interesting contributors to aging, and they provide a new perspective in understanding the aging process. As a person ages, progressive changes in intestinal tract physiology, the intestinal mucosal immune system, lifestyle changes (particularly in diet and exercise), medication, malnutrition, inflammation, and immune senescence may change the diversity, composition, and functional features of the gut microbiota. Data from animal models demonstrate that age-related microbial dysbiosis contributes to intestinal permeability, systemic inflammation, and premature mortality. Though the cause-and-effect relationship is unclear, age-related microbial dysbiosis is linked to unhealthy aging and geriatric syndromes, which include frailty. Identifying specific changes in frailty-related gut microbiota is essential in developing microbiome-based diagnostic and therapeutic strategies.

In this review, we first describe the relevant changes in gut microbiota related to aging and frailty. Subsequently, we summarize recent findings on the possible role of chronic low-grade inflammation in frailty and how microbial dysbiosis is involved in its pathogenesis, including frailty-related inflammation.

Recent evidence has emerged of the role of perineuronal nets (PNNs) in neuroplasticity - the ability of the brain to learn and adapt - and to make memories. PNNs are cartilage-like structures that mostly surround inhibitory neurons in the brain. Their main function is to control the level of plasticity in the brain. They appear at around five years old in humans, and turn off the period of enhanced plasticity during which the connections in the brain are optimised. Then, plasticity is partially turned off, making the brain more efficient but less plastic.

PNNs contain compounds known as chondroitin sulphates. Some of these, such as chondroitin 4-sulphate, inhibit the action of the networks, inhibiting neuroplasticity; others, such as chondroitin 6-sulphate, promote neuroplasticity. As we age, the balance of these compounds changes, and as levels of chondroitin 6-sulphate decrease, so our ability to learn and form new memories changes, leading to age-related memory decline.

Researchers investigated whether manipulating the chondroitin sulphate composition of the PNNs might restore neuroplasticity and alleviate age-related memory deficits. To do this, the team looked at 20-month old mice - considered very old - and using a suite of tests showed that the mice exhibited deficits in their memory compared to six-month old mice. The team treated the ageing mice using a 'viral vector', a virus capable of reconstituting the amount of 6-sulphate chondroitin sulphates to the PNNs and found that this completely restored memory in the older mice, to a level similar to that seen in the younger mice.

Endothelin-1 (ET-1) is a potent vasoconstrictor synthesized by vascular endothelial cells that is normally present at low plasma concentrations. ET-1 plays a significant role in kidney physiology and pathology, highlighted by the fact that ET-1 transgenic mice undergo spontaneous kidney fibrosis even in the absence of hypertension. Ageing is associated with an increase in ET-1 levels in the renal vasculature. Elevated ET-1 can increase reactive oxygen species (ROS), which in turn can increase the uptake of oxidized low-density lipoprotein (ox-LDL) by increasing the expression of its cognate receptor lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), cumulatively contributing to endothelial dysfunction. Indeed, pre-clinical studies with endothelin receptor antagonists have shown promising results in alleviating ageing-induced impairment of renal function.

Caloric restriction (CR) can reduce the ageing process and related organ dysfunction in most species. CR without malnutrition is a dietary regimen that delays ageing and extends the lifespan. More importantly, studies in mice and rat models of ageing have shown that CR exerts significant cerebrovascular protective effects, improves cortical microvascular density and endothelial function, and counteracts ageing-induced alterations in renal function, including glomerulosclerosis and alterations in glomerular filtration. CR also improved vascular health by eliciting changes in the levels of circulating neuroendocrine factors.

Given this background, the objective of the current study was to investigate whether CR counteracts ageing-induced alterations in renal function and inflammatory cytokines by impacting ET-1 levels. We found that ET-1 messenger RNA (mRNA) and protein expression were increased ex vivo in the renal artery segments of 12-month-old rats compared to 2-month-old rats, which was reversed when rats were subjected to CR. Functional assays showed that CR alleviated renal dysfunction and decreased the expression of pro-inflammatory cytokines by decreasing ET-1 expression.

Dementia and osteoporosis are highly prevalent in the elderly population and often coexist. Individuals with dementia are at high risk of osteoporosis and hip fracture. It has been estimated that approximately 40% of patients with hip fracture have a prior diagnosis of dementia. The risk of hip fracture in Alzheimer's disease was recently reported in a meta-analysis of nine cohorts from the United States, Canada, and the UK to be over twofold compared to those without dementia. Furthermore, this study also demonstrated that hip bone mineral density (BMD) was lower in those affected compared to controls.

Notably, a recent study has demonstrated increased risk of dementia following both hip and non-hip fractures. Although the risk of dementia was highest following hip fracture (60%), vertebral (47%), lower (35%), and upper limb (29%) fractures were also associated with increased risk. These findings are particularly important as non-hip fractures are very common, affecting two in five women and one in three men after the age of 60 years.

The nature of the association between osteoporosis and dementia is not entirely clear. Most authors to date believe that the association between these two common conditions is likely driven by common risk factors such as old age, sedentary lifestyle, physical decline, vitamin D insufficiency, sarcopenia, and propensity to falls. However, there is some evidence that suggests that hip fracture per se may lead to complications which directly precipitate dementia development. Furthermore, at least two studies have shown a significant association between low BMD or bone loss and subsequent cognitive decline in postmenopausal women. However, studies investigating the longitudinal long-term association between cognitive decline and both bone loss and fracture risk are lacking.

This study aimed to determine the association between: (i) cognitive decline and bone loss; and (ii) clinically significant cognitive decline on Mini Mental State Examination (MMSE) over the first 5 years and subsequent fracture risk over the following 10 years. A total of 1741 women and 620 men aged ≥65 years from the population-based Canadian Multicentre Osteoporosis Study were followed from 1997 to 2013. Over 95% of participants had normal cognition at baseline. After multivariable adjustment, cognitive decline was associated with bone loss in women but not men. Approximately 13% of participants experienced significant cognitive decline by year 5. In women, fracture risk was increased significantly. There were too few men to analyze. There was a significant association between cognitive decline and both bone loss and fracture risk, independent of aging, in women