Among men and women between the ages of 75 and 80, muscle strength, walking speed, reaction speed, verbal fluency, reasoning and working memory are nowadays significantly better than they were in people at the same age born earlier. In lung function tests, however, differences between cohorts were not observed. "The cohort of 75- and 80-year-olds born later has grown up and lived in a different world than did their counterparts born three decades ago. There have been many favourable changes. These include better nutrition and hygiene, improvements in health care and the school system, better accessibility to education and improved working life."

The results suggest that increased life expectancy is accompanied by an increased number of years lived with good functional ability in later life. The observation can be explained by slower rate-of-change with increasing age, a higher lifetime maximum in physical performance, or a combination of the two. "The results suggest that our understanding of older age is old-fashioned. From an aging researcher's point of view, more years are added to midlife, and not so much to the utmost end of life. Increased life expectancy provides us with more non-disabled years, but at the same time, the last years of life comes at higher and higher ages, increasing the need for care. Among the ageing population, two simultaneous changes are happening: continuation of healthy years to higher ages and an increased number of very old people who need external care."

Whether increased life expectancy is accompanied by increased functional capacity in older people at specific ages is unclear. We compared similar validated measures of maximal physical performance in two population-based older cohorts born and assessed 28 years apart. Participants in the first cohort were born in 1910 and 1914 and were assessed at age 75 and 80 years, respectively (N=500, participation rate 77%). Participants in the second cohort were born in 1938 or 1939 and 1942 or 1943 and were assessed at age 75 and 80 years, respectively (N=726, participation rate 40%). Maximal walking speed, maximal isometric grip strength and knee extension strength, lung function measurements; forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) were assessed. Data on non-participation were systematically collected.

Walking speed was on average 0.2-0.4 m/s faster in the later than earlier cohort. In grip strength, the improvements were 5-25%, and in knee extension strength 20-47%. In FVC, the improvements were 14-21% and in FEV1 0-14%. The later cohort showed markedly and meaningfully higher results in the maximal functional capacity tests, suggesting that currently 75- and 80-year old people are living to older ages nowadays with better physical functioning.

The world's population is ageing rapidly, presenting an urgency to address the health problems of the aged. Critical insights on these problems can be gained by examining how the ageing process has been shaped over evolutionary time, and how it is influenced by different environments and lifestyles. In this issue, we feature research conducted on humans in small-scale societies and on our closest primate relatives to ask how bodies, minds, and behaviour age outside of the usual research settings. These contributions shed light on the complex relationship between ageing and disease and offer clues to the social and ecological predictors of successful ageing.

Researchers examined cardiovascular profiles in chimpanzees living in African sanctuaries. These chimpanzees occupy large rainforest enclosures, consume a diet of fruits and vegetables, and generally experience conditions more similar to a wild chimpanzee lifestyle. They measured blood lipids, body weight and body fat in 75 sanctuary chimpanzees during annual veterinary health check-ups, and then compared them to published data from laboratory-living chimpanzees. Free-ranging chimpanzees in sanctuaries exhibited lower body weight and lower levels of lipids, both risk factors for human cardiovascular disease. Some of these disparities increased with age, indicating that the free-ranging chimpanzees stayed healthy as they got older.

Prior work suggested that chimpanzees have very high levels of blood lipids that are cardiovascular risk factors - higher than humans in post-industrial societies in some cases. The work also showed that chimpanzees living a naturalistic life have much lower levels even as they age, providing a new reference for understanding human health. In biomedical research labs, chimpanzees have more limited space and often consume a processed diet (food such as primate chow), unlike wild chimpanzees.

Many humans live to see their 70s and 80s, some even reach 100 years old. But life is much shorter for our closest animal relatives. Chimpanzees, for example, rarely make it past age 50, despite sharing almost 99% of our genetic code. While advances in medicine and nutrition in the last 200 years have added years to human lifespans, a new study suggests there could be a more ancient explanation why humans are the long-lived primate.

Studies have shown that certain sites along our DNA gain or lose chemical tags called methyl groups in a way that marks time, like a metronome. The changes are so consistent that they can be used as an "aging clock" to tell a person's age to within less than four years. The new study marks the first time such age-related changes have been analyzed in chimpanzees. Researchers analyzed some 850,000 of these sites in blood from 83 chimpanzees aged 1 to 59. Sure enough, they found that aging leaves its mark on the chimpanzee genome, just as it does in humans. More than 65,000 of the DNA sites the scientists scrutinized changed in a clock-like way across the lifespan, with some gaining methylation and others losing it.

The pattern was so reliable that the researchers were able to use DNA methylation levels to tell a chimpanzee's age to within 2.5 years, which is much more accurate than current methods for estimating a wild animal's age by the amount of wear on their molars. When the researchers compared the rates of change they found in chimps with published data for humans, the epigenetic aging clock ticked faster for chimpanzees.

One of the key issues facing public healthcare is the global trend of an increasingly ageing society which continues to present policy makers and caregivers with formidable healthcare and socio-economic challenges. Ageing is the primary contributor to a broad spectrum of chronic disorders all associated with a lower quality of life in the elderly. In 2019, the Chinese population constituted 18% of the world population, with 164.5 million Chinese citizens aged 65 and above (65+), and 26 million aged 80 or above (80+). China has become an ageing society, and as it continues to age it will continue to exacerbate the burden borne by current family and public healthcare systems.

Europe is characterized by three types of care provision: 1) 'crowding out', whereby the state largely replaces family care; 2) 'crowding in', whereby the state promotes family care; 3) 'mixed responsibility', whereby both the state and the family take a joint responsibility for care, yet have separate functions. In China, family is still the traditional provider for elderly care. In order to deal with the ongoing boom in the elderly population, the Chinese government has put more effort into funding research on ageing and its related diseases in recent decades. More attention has been placed on the development of pharmacological strategies against ageing, organ degeneration and major ageing-related diseases.

Targeting classic longevity pathways

Calorie restriction (CR) was first demonstrated as an effective way to extend lifespan in rodents, however the physiological mechanisms behind its anti-ageing effectiveness were not fully understood at the time, and remain uncertain. Later studies have suggested that CR might extend lifespan by regulating insulin-like growth factor (IGF) and mammalian target of rapamycin (mTOR) pathways. Metformin is primarily known for treating type 2 diabetes, with its underlying molecular mechanisms leading to the to down-regulation of IGF-1 signaling, and the inhibition of cellular proliferation, mitochondrial biogenesis, reactive oxygen species (ROS) production, DNA damage, activity of the mTOR pathway, etc. Acarbose has been shown to partially mimic the effects of CR and extend lifespan in mice by controlling blood sugar and slowing carbohydrate digestion. Rapamycin, a well-known inhibitor of mTOR, has shown life-extending effects in all model organisms and postpones the onset of age-associated diseases.

NAD+ boosters

Nicotinamide adenine dinucleotide (NAD+) is a fundamental molecule in human life and health; while there is an age-dependent reduction of NAD+, NAD+ augmentation extends lifespan and improves healthspan in different animal models as well as shows potential to treat different neurodegenerative diseases based on phase I clinical trials. NAD+ precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) have emerged as promising approaches for intervention against ageing phenotypes and age-related diseases. Supplementation via these precursors can elevate NAD+ level in vivo and improve glucose metabolism, mitochondria biogenesis, DNA repair, neovascularization, and neuroprotection.

Senolytics

Senescent cells accumulate in aged tissues and this accumulation is considered one of the driving forces of ageing. Senolytics are a class of molecules specifically designed to induce apoptosis of these senescent cells. Clearing senescent cells in mice has been shown to substantially alleviate ageing phenotypes, producing potent therapeutic effects in ageing-related diseases such as Alzheimer's disease, atherosclerosis, and osteoarthritis. The senolytic cocktail of dasatinib plus quercetin (DQ) decreased naturally occurring senescent cells, improved mobility, and reduced the risk of mortality. While clinical trials on senolytic drugs are mainly conducted in the USA, the concept of reducing senescent cells to delay the ageing progress has attracted interest from all over the world. Since 2016, the National Natural Science Foundation of China (NSFC) has set up special programs, providing millions to support research on cellular senescence and organ degeneration.

One of most profound revelations of recent advances in science is that biological systems can be completely rejuvenated. Indeed, just a few years ago, reversing the deleterious changes that accumulate with age in their entirety was simply unimaginable. Yet, we now know that this is possible, whether we consider the conversion of somatic cells to induced pluripotent stem cells (iPSCs) or the natural reversal of age of the germline with each generation. These two processes converge somewhere during early development at the point here proposed to be termed the 'ground zero.' It is here that both organismal life and aging begin.

It is often discussed that, because the germline is immortal, it does not age; this notion dates to the 19th century, when August Weismann proposed the separation of ageless germline and aging body. However, at the time of conception, the contributing human germline has typically been maintained in a metabolically active state for two or more decades and must have accumulated damage, such as metabolic by-products, epimutations, and modified irreplaceable proteins. In other words, it has become biologically older than its earlier, embryonic state.

Although the germline biological age at the time of conception is expected to be much younger than that of somatic tissues of the same organism, and although some of the accumulated damage may be removed by designated molecular systems, rejuvenation in the prezygotic state could only be partial because, in the absence of cell division (as in the oocyte), there are always more damage forms than the means of protecting against them. Also, although some germ cells may accumulate more damage than others and therefore may lead to early mortality and abnormalities in the offspring (this damage will also increase with the age of the host), all germ cells unavoidably accumulate some damage. Thus, for the new life to begin in the same young state as in the previous generation, the zygote must somehow remove this damage and decrease its biological age to the level of the germline age in the previous generation. In other words, it appears that the germline ages during development and adult life, and then it is rejuvenated in the offspring after conception.

All this leads to a model wherein early embryos are gradually rejuvenated, for example, by extending their telomeres, erasing epigenetic marks, and clearing up and diluting molecular damage, and this continues up to a particular time during early development. Conception represents a starting point for this process, culminating in the state of the lowest biological age, the ground zero of organismal life and aging. In effect, the period from conception to this stage may be viewed as a preparatory stage, which is associated with damage clearance and rejuvenation, for subsequent development of the organism.

The ground zero model extends and modifies Weismann's notion of heritable immortal germline and noninheritable aging body by positing that (i) both body and germline can age; (ii) both body and germline can be rejuvenated; (iii) body and germline can be brought to a common state characterized by the lowest biological age, ground zero; and (iv) age can be reversed without the need to have a separate body and germline. The proposed model is currently based on in vitro experiments and application of epigenetic and other clocks to assess biological age and should be extended to experimental organismal biology. Understanding the nature and mechanisms of rejuvenation, defining the exact point of ground zero, and discovering ways to manipulate the lowest age may provide opportunities for dramatic advances in human biology and medicine

Glucosepane is among the most abundant AGEs found in human tissues. It is formed from lysine, arginine, and glucose, and it is over an order of magnitude more abundant than any other AGE crosslink in extracellular matrix (ECM). Notably, glucosepane levels have been shown to correlate with various disease states, including diabetic retinopathy, microalbuminuria, and neuropathy. While the exact mechanisms behind glucosepane-mediated dysfunction remain unclear, it is believed to impair the functional and mechanical properties of proteins in the ECM and interfere with proteolytic degradation of collagen.

To date, the primary method for identifying glucosepane in tissues has required exhaustive enzymatic degradation followed by high pressure liquid chromatography-mass spectrometry (LC/MS). Although these protocols have proven effective in quantifying glucosepane in bulk tissue extracts, they are labor-intensive and the degradation process destroys the tissue architecture, making it difficult to examine the localization of glucosepane.

In recent years, anti-AGE antibodies have emerged as useful tools for studying AGEs and have the advantage of being compatible with the evaluation of intact tissues, enabling immunohistochemical staining and imaging procedures. Several anti-AGE antibodies have been produced by immunization of animals with AGEs generated either from total synthesis or through in vitro glycation methods. Such methods involve the incubation of an immunogenic carrier protein, such as BSA, with glucose or other reactive sugar metabolites. Reaction conditions that generate glucosepane are known also to generate a range of AGE by-products, including carboxymethyllysine. These in vitro preparation methods are unlikely to produce antibodies that are specific for glucosepane, although no such studies have been reported.

To avoid this expected complication, we decided to synthesize homogeneous, synthetic glucosepane immunogens. Herein, we describe the development and characterization of the first antibodies known to selectively recognize glucosepane. To this end, we have created a synthetic glucosepane immunogen that closely resembles glucosepane found in vivo and used it to generate a polyclonal antibody serum that recognizes glucosepane both in vitro and in ex vivo tissue samples. We have demonstrated that the antibodies can bind to glucosepane with high degrees of specificity and sensitivity through ELISA studies and have employed these antibodies in immunohistochemical experiments.

Interestingly, these latter studies demonstrate that glucosepane accumulates within sub-components of the retina, specifically the retinal pigment epithelium (RPE), Bruch's membrane, and choroid, which are anatomic areas highly affected by AMD and diabetic retinopathy.

Macroautophagy, hereafter referred to as "autophagy," is an evolutionarily conserved pathway involving the engulfment of cytosolic contents by a lipid membrane for recycling of nutrients or removal of harmful aggregates, microbes, and organelles. Mitophagy is one form of macroautophagy that involves selectively targeting and engulfing mitochondria for removal through lysosomal degradation. Activation of this pathway is a result of mitochondria being damaged beyond the capabilities of other quality control methods or in instances in which the cell needs to get rid of mitochondria for metabolic or developmental purposes.

Mitophagy is important for any cell that contains mitochondria. When moving from this idea of a nondescript eukaryotic cell to differentiated, specific cells that make up our body's organs, certain tissues become focal points for discussion. These include muscle cells and neurons because of their specific functions, metabolism, and energy requirements. These cells make up organs with high energy consumption and vulnerability, and slight perturbations in homeostasis can lead to pronounced effects. Although we focus on these two cell types, mitophagy is important in all organs where mitochondria play important roles.

The deep molecular understanding of mitophagy we have stems from the thorough investigation into PINK1 and Parkin, which are both major recessive risk factors for developing early onset Parkinson's disease (PD). The unique structure of the neuron creates an environment where not only does the mitochondrial pool have to be healthy, but it also must be properly transported down the axon to quite distant sites where ATP production and calcium buffering are its two most important functions. An aged nervous system coupled with a decline in mitophagy leads to accumulation of bad mitochondria and is a hallmark of neurodegeneration.

Until recently, surprisingly little evidence directly linked mitophagy to the most common neurodegenerative disease, Alzheimer's disease (AD). Historically, PD etiology was more focused on defective mitophagy, whereas investigation of AD has focused on accumulation of amyloid-β (Aβ) plaques and phospho-tau neurofibrillary tangles. Recent studies have shown that mitophagy is, in fact, affected in AD and, more important, that inducing mitophagy could benefit the pathological and cognitive outcomes. Models of toxic Aβ and tau were shown to impair mitophagy, and increasing mitophagy helped to reduce the plaque and neurofibrillary tangle burden in Caenorhabditis elegans and mouse models.

As with most therapeutics that control a biological process, increasing levels of mitophagy must be carefully controlled because passing an upper limit would induce cell death, so careful modulation rather than constitutive activation would be ideal for this style of treatment. Physiologically relevant stimulation through NAD+ supplementation has been effective in mouse and C. elegans studies in AD. By supplementing with a molecule that is already present in the body, the safety concerns are greatly reduced. Alternatively, by removing the brakes on the mitophagy system, such as the deubiquitinating enzymes, we would also increase levels of basal mitophagy. Regardless of the treatment approach, the ideal therapy will be targeted to the dysfunctional organ because affecting the balance of mitophagy in off-target organs that do not have mitochondrial dysfunction will create additional problems.

Many studies have shown that in patients with type 2 diabetes, chronic administration of metformin causes side effects such as abdominal or stomach pain, diarrhea, early satiety, decreased appetite, risk of vitamin B-12 deficiency, and lactic acidosis. In the current study, we treated non-diabetic mice with metformin for 10 months. Unequivocally, our results show that chronic metformin treatment may lead to severe disabilities, including cancer, cataracts, and dermatitis. Studies in nematodes and other smaller organisms suggest that the side effects of chronic metformin treatment may be caused by changes in the gut microbiome.

To avoid the side effects of metformin, we treated mice with metformin by tail vein injection, which is believed to have little effect on the composition of gut microbes. Interestingly, it appears that metformin treatment by tail vein injection results in better cognitive function performance than oral administration. Consequently, we speculate that gut microbes may play an important role in mediating the side effects of metformin, and this potential role needs to be further explored. The beneficial effects of metformin on cognitive function are associated with the restoration of vascular integrity, producing a richer cerebral blood flow, as well as activation of neurogenesis in the subventricular zone. The mechanism of metformin administration enhanced glycolysis through increased mRNA expression of GAPDH, which ultimately increased angiogenesis and neurogenic potential of neural stem cells.

To avoid the side effects of metformin, our study proposes careful reconsideration of lower doses of metformin treatment by tail vein injection for translational research. Altogether, our study shows an improved method for metformin treatment, which might contribute to a reduction in the side effects of metformin and lead to better therapeutic value for anti-aging in humans.

Researchers around the world have been puzzled by the different symptoms and varied disease pathways of Parkinson's patients. A major study has now identified that there are actually two types of the disease. Although the name may suggest otherwise, Parkinson's disease is not one but two diseases, starting either in the brain or in the intestines, which explains why patients with Parkinson's describe widely differing symptoms. "With the help of advanced scanning techniques, we've shown that Parkinson's disease can be divided into two variants, which start in different places in the body. For some patients, the disease starts in the intestines and spreads from there to the brain through neural connections. For others, the disease starts in the brain and spreads to the intestines and other organs such as the heart."

Parkinson's disease is characterised by slow deterioration of the brain due to accumulated alpha-synuclein, a protein that damages nerve cells. This leads to the slow, stiff movements which many people associate with the disease. In the study, the researchers have used advanced PET and MRI imaging techniques to examine people with Parkinson's disease. People who have not yet been diagnosed but have a high risk of developing the disease are also included in the study. The study showed that some patients had damage to the brain's dopamine system before damage in the intestines and heart occurred. In other patients, scans revealed damage to the nervous systems of the intestines and heart before the damage in the brain's dopamine system was visible.

"It has long since been demonstrated that Parkinson's patients have a different microbiome in the intestines than healthy people, without us truly understanding the significance of this. Now that we're able to identify the two types of Parkinson's disease, we can examine the risk factors and possible genetic factors that may be different for the two types. The next step is to examine whether, for example, body-first Parkinson's disease can be treated by treating the intestines with fecal microbiota transplantation or in other ways that affect the microbiome. The discovery of brain-first Parkinson's is a bigger challenge. This variant of the disease is probably relatively symptom-free until the movement disorder symptoms appear and the patient is diagnosed with Parkinson's. By then the patient has already lost more than half of the dopamine system, and it will therefore be more difficult to find patients early enough to be able to slow the disease."

Cell transplant has been an attractive potential therapy for cardiovascular disease; however, poor cell engraftment limits efficacy of the approach. We here compared transplanting a mixture of human induced pluripotent stem cell-derived cardiomyocytes, endothelial cells, and smooth muscle cells to transplant of exosomes produced by these cells in a pig model of myocardial infarction. They saw similar improvements in cardiac function in cell, cell fragment, and exosome transplant groups without evidence of increased arrhythmogenicity.

We compared the efficacy of treatment with a mixture of cardiomyocytes (CMs; 10 million), endothelial cells (ECs; 5 million), and smooth muscle cells (SMCs; 5 million) derived from human induced pluripotent stem cells (hiPSCs), or with exosomes extracted from the three cell types, in pigs after myocardial infarction (MI). Female pigs received sham surgery; infarction without treatment (MI group); or infarction and treatment with hiPSC-CMs, hiPSC-ECs, and hiPSC-SMCs (MI + Cell group); with homogenized fragments from the same dose of cells administered to the MI + Cell group (MI + Fra group); or with exosomes (7.5 mg) extracted from a 2:1:1 mixture of hiPSC-CMs:hiPSC-ECs:hiPSC-SMCs (MI + Exo group). Cells and exosomes were injected into the injured myocardium.

In vitro, exosomes promoted EC tube formation and microvessel sprouting from mouse aortic rings and protected hiPSC-CMs by reducing apoptosis, maintaining intracellular calcium homeostasis, and increasing adenosine 5′-triphosphate. In vivo, measurements of left ventricular ejection fraction, wall stress, myocardial bioenergetics, cardiac hypertrophy, scar size, cell apoptosis, and angiogenesis in the infarcted region were better in the MI + Cell, MI + Fra, and MI + Exo groups than in the MI group 4 weeks after infarction. The frequencies of arrhythmic events in animals from the MI, MI + Cell, and MI + Exo groups were similar. Thus, exosomes secreted by hiPSC-derived cardiac cells improved myocardial recovery without increasing the frequency of arrhythmogenic complications and may provide an acellular therapeutic option for myocardial injury.

As amyloid-β (Aβ) accumulates in a person's brain during the long preclinical stage of Alzheimer's disease, deficits in learning emerge prior to impairments in episodic memory, according to a new study. Cognitively normal people who tested positive for brain amyloid learned fewer Chinese characters over a six-day period than their amyloid-negative peers. Their learning deficit was more pronounced than any form of memory impairment, and it correlated with smaller hippocampi.

In public parlance, memory loss has become almost synonymous with AD. Alas, during the disease's preclinical stage-which scientists are trying to target for intervention - memory loss creeps up slowly and varies from person to person. Hence trials enrolling people at those stages struggle to assess clinical efficacy of the drug under investigation. New tests are sorely needed.

The new study tested 80 cognitively normal participants - 42 amyloid-negative, 38 amyloid-positive - and included other cognitive and neuroimaging measures. As had been seen in the previous cohort, amyloid-negative participants learned the meaning of Chinese characters faster, with accuracy differences between the groups emerging on day one and growing in each session. The two groups' average rate of learning over the entire six days differed by more than two standard deviations. In contrast, the groups barely differed on their most recent scores on any test of episodic memory. Among Aβ-positive participants only, those who learned the Chinese characters more slowly had smaller hippocampi and larger brain ventricles, suggesting less gray-matter volume.

SARS-CoV-2 is a novel betacoronavirus which infects the lower respiratory tract and can cause coronavirus disease 2019 (COVID-19), a complex respiratory distress syndrome. Epidemiological data show that COVID-19 has a rising mortality particularly in individuals with advanced age. Identifying a functional association between SARS-CoV-2 infection and the process of biological aging may provide a tractable avenue for therapy to prevent acute and long-term disease.

Here, we discuss how cellular senescence - a state of stable growth arrest characterized by pro-inflammatory and pro-disease functions - can hypothetically be a contributor to COVID-19 pathogenesis, and a potential pharmaceutical target to alleviate disease severity. First, we define why older COVID-19 patients are more likely to accumulate high levels of cellular senescence. Second, we describe how senescent cells can contribute to an uncontrolled SARS-CoV-2-mediated cytokine storm and an excessive inflammatory reaction during the early phase of the disease. Third, we discuss the various mechanisms by which senescent cells promote tissue damage leading to lung failure and multi-tissue dysfunctions. Fourth, we argue that a high senescence burst might negatively impact on vaccine efficacy.

Measuring the burst of cellular senescence could hypothetically serve as a predictor of COVID-19 severity, and targeting senescence-associated mechanisms prior and after SARS-CoV-2 infection might have the potential to limit a number of severe damages and to improve the efficacy of vaccinations.

Alzheimer's disease (AD) is a progressive, late-onset dementia with no effective treatment available. Recent studies suggest that AD pathology is driven by age-related changes in metabolism. Alterations in metabolism, such as placing patients on a ketogenic diet, can alter cognition by an unknown mechanism. One of the ketone bodies produced as a result of ketogenesis, β-hydroxybutyrate (BHB), is known to inhibit NLRP3 inflammasome activation. Therefore, we tested if BHB inhibition of the NLRP3 inflammasome reduces overall AD pathology in the 5XFAD mouse model of AD.

Here, we find BHB levels are lower in red blood cells and brain parenchyma of AD patients when compared with non-AD controls. Furthermore, exogenous BHB administration reduced plaque formation, microgliosis, PYCARD speck formation, and caspase-1 activation in the 5XFAD mouse model of AD. Taken together, our findings demonstrate that BHB reduces AD pathology by inhibiting NLRP3 inflammasome activation. Additionally, our data suggest dietary or pharmacological approaches to increase BHB levels as promising therapeutic strategies for AD.

Two recent comprehensive meta-analyses assessed the association of general adiposity, represented by body mass index, with the risk of all cause mortality in the general population. The results indicated that a U shaped and a J shaped association existed between body mass index and the risk of all cause mortality in the general population. The lowest risk was observed for a body mass index of 22-23 in healthy never smokers. Body mass index is easy to obtain and so is the most frequent anthropometric measure used to investigate obesity-mortality and obesity-morbidity associations.

The validity of body mass index as an appropriate indicator of obesity has been questioned. Research suggests that body mass index does not differentiate between lean body mass and fat mass; therefore, when using body mass index as a measure, inaccurate assessment of adiposity could occur. Additionally, the most important limitation of body mass index is that it does not reflect regional body fat distribution. Existing evidence suggests that central obesity and abdominal deposition of fat is more strongly associated with cardiometabolic risk factors and chronic disease risk than overall obesity.

Taking this evidence into account, indices of central obesity might be more accurate than body mass index when estimating adiposity, and therefore could be more closely and strongly associated with the risk of mortality. We aimed to perform a systematic review and dose-response meta-analysis of prospective cohort studies to investigate the association of indices of central fatness with the risk of all cause mortality in the general population, in never smokers, and in healthy never smokers. The indices of central fatness were waist circumference, hip circumference, thigh circumference, waist-to-hip ratio, waist-to-height ratio, waist-to-thigh ratio, body adiposity index, and A body shape index.

Indices of central fatness including waist circumference, waist-to-hip ratio, waist-to-height ratio, waist-to-thigh ratio, body adiposity index, and A body shape index, independent of overall adiposity, were positively and significantly associated with a higher all cause mortality risk. Larger hip circumference and thigh circumference were associated with a lower risk. The results suggest that measures of central adiposity could be used with body mass index as a supplementary approach to determine the risk of premature death.

Two common neurodegenerative diseases - ALS and frontotemporal lobar degeneration, or FTLD - result from reduced transportation of RNA by the protein TDP-43, which ultimately disrupts neuron function. Because one of the biggest physiological changes in both ALS and FTLD is the disappearance of TDP-43 from the nucleoli of neurons, the team focused their research on finding out what TDP-43 normally does. TDP-43 is known to bind to RNA, and the team's first experiment showed that in neurons, TDP-43 attaches to RNA that codes for pieces of ribosomes, which are necessary for making proteins from RNA code.

"We discovered TDP-43 in axons and that it binds to ribosomal protein messenger RNA. That was strong support for the idea that TDP-43 carries the RNA to the axon where it can be used to make ribosomal proteins. This would allow local synthesis of proteins at ribosomes built in axons." Indeed, further experiments confirmed that hypothesis and showed that when TDP-43 was missing, the RNA in question could not be transported to the axon.

But what happens if the RNA cannot be transported? The researchers examined axon growth in culture as well as in mouse embryos. They found that in both cases, axon extension and outgrowth were stunted when TDP-43 was missing. However, outgrowth could be restored by forcing the neurons to overproduce ribosomal proteins. "Now that we understand TDP-43's role in transporting the ribosomal protein messenger RNA, it should help us develop new strategies and new targets for ALS and FTLD treatments. Our results in reversing stunted axon extension in mouse embryos is promising, but is just a first step."

The loss of cognitive function in Alzheimer's disease is pathologically linked with neurofibrillary tangles, amyloid deposition, and loss of neuronal communication. Cerebral insulin resistance and mitochondrial dysfunction have emerged as important contributors to pathogenesis supporting our hypothesis that cerebral fructose metabolism is a key initiating pathway for Alzheimer's disease.

Fructose is unique among nutrients because it activates a survival pathway to protect animals from starvation by lowering energy in cells in association with adenosine monophosphate degradation to uric acid. The fall in energy from fructose metabolism stimulates foraging and food intake while reducing energy and oxygen needs by decreasing mitochondrial function, stimulating glycolysis, and inducing insulin resistance. When fructose metabolism is overactivated systemically, such as from excessive fructose intake, this can lead to obesity and diabetes.

Herein, we present evidence that Alzheimer's disease may be driven by overactivation of cerebral fructose metabolism, in which the source of fructose is largely from endogenous production in the brain. Thus, the reduction in mitochondrial energy production is hampered by neuronal glycolysis that is inadequate, resulting in progressive loss of cerebral energy levels required for neurons to remain functional and viable. In essence, we propose that Alzheimer's disease is a modern disease driven by changes in dietary lifestyle in which fructose can disrupt cerebral metabolism and neuronal function. Inhibition of intracerebral fructose metabolism could provide a novel way to prevent and treat this disease.