At this point, I suspect it will surprise no-one who follows the field to learn that the accumulation of senescent cells is a significant cause of degenerative disc disease. The evidence from a mouse study that is provided in the open access paper here doesn't quite rise to establishing that claim, but it is compelling nonetheless. Given the role of cellular senescence in arthritis, a disease of localized chronic inflammation, it is logical to also expect a role in the degeneration of intervertebral discs, as this is also a condition of aging in which inflammation seems important.

Senescent cells, even while present in only comparatively small numbers, generate a potent mix of molecules that spurs chronic inflammation and is destructive of surrounding tissue structure. Fortunately early senolytic compounds, those shown to destroy a sizable fraction of senescent cells cells in animal studies, are cheap and readily available to anyone willing to try this self-experiment. It is just a pity that so few older people know this at the present time - the hundreds of millions worldwide who are suffering when perhaps they need not be.

Age-related changes in the intervertebral discs are the predominant contributors to back pain, a common physical and functional impairment experienced by older persons. Cellular senescence, a process wherein cells undergo growth arrest and chronically secrete numerous inflammatory molecules and proteases, has been reported to cause decline in the health and function of multiple tissues with age. Although senescent cells have been reported to increase in intervertebral degeneration (IDD), it is not known whether they are causative in age-related IDD.

To examine the impact of senescent cells on age-associated IDD, we used p16-3MR transgenic mice, which enables the selective removal of p16Ink4a-positive senescent cells by the drug ganciclovir. Disc cellularity, aggrecan content and fragmentation alongside expression of inflammatory cytokine (IL-6) and matrix proteases (ADAMTS4 and MMP13) in discs of p16-3MR mice treated with ganciclovir and untreated controls were assessed. In aged mice, reducing the percent of senescent cells decreased disc aggrecan proteolytic degradation and increased overall proteoglycan matrix content along with improved histological disc features. Additionally, reduction of senescent cells lowered the levels of MMP13, which is purported to promote disc degenerative changes during aging.

The findings of this study suggest that systemic reduction in the number of senescent cells ameliorates multiple age-associated changes within the disc tissue. Cellular senescence could therefore serve as a therapeutic target to restore the health of disc tissue that deteriorates with age.

Link: https://doi.org/10.1111/acel.12927

Researchers here process the enormous set of health data found in the UK Biobank to conclude that there is comparatively little sign of cognitive decline in cohorts younger than age 65. After that, loss of function sets in quite rapidly, however. This is good news for those of us taking good care of our health, and who have a long time yet before reaching 65. Not so great for the older contingent in the population, but we really don't need any more incentives than already exist in order to forge ahead with the development of rejuvenation therapies. Repair of the damage that causes aging, and aging of the brain in particular, is the only path forward likely to produce meaningful results in the clinic over the next ten to twenty years.

Age is a key risk factor for cognitive performance. Cognitive decline is common in older ages but recently there has been interest in understanding the age at which significant decline in cognitive abilities begins. Such knowledge has implications for the design of behavioral or pharmacological interventions since they are more likely to work if they are applied when, or even years before, individuals first begin to experience decline. Efforts to date are often based on cross-sectional studies which may be confounded by 'cohort effects'. Longitudinal studies suggest evidence of cognitive decline in middle age but that age trajectories differ by sex and cognition domain or task.

Longitudinal data that span many decades generally report minimal cognitive decline before the age of 65, but such studies are rare and also subject to limitations including small sample size, selection attrition, and retest or practice effects. Researchers examined cognitive decline among ~2,500 participants aged 25 to 95 years at recruitment in the Midlife in the United States (MIDUS) study, and all cognitive domains measured showed significant but small declines over 9 years, with differences in the timing and extent of change. The largest analysis to-date included a 10 year follow-up of ~7,400 participants aged 45-70 at recruitment of the Whitehall Study. The design of this study allowed for cross-sectional and longitudinal analysis. For the former analysis, performance on several tests were progressively lower with older age categories. In longitudinal analyses, there was some evidence of greater decline at older ages and of a linear trend in decline with increasing age for some of the tests, particularly in men.

UK Biobank is a large population cohort of adults who underwent medical, sociodemographic, mental health and cognitive assessment in 2006-2010 and are being followed up at intervals. The large age-distribution and follow-up enables cross-sectional as well as longitudinal analysis of age. In the current study of individuals aged 38 to 73 at baseline, we observed significantly lower performance on memory, attention, and processing tasks across successive age groups. Reasoning scores, based on the fluid intelligence test, were higher with successive age group until 60, then dropped to less than that of under 45 year olds. Longitudinal analysis of a subset of individuals with repeated measures of four tests showed linear declines in visual memory and processing speed tasks with age but of a much lesser degree than those observed in cross-sectional analyses. Decline rates in reasoning and prospective memory did not significantly differ with age. Taken together, our findings suggest that decline in cognitive abilities before age 65 is evident but small, and that observed cross-sectional differences in cognition from middle to older adult years may be due largely to age cohort effects.

Link: https://doi.org/10.1371/journal.pone.0213948

Rising levels of oxidative stress occur with aging. This term describes the presence of excessive numbers of oxidative molecules, reacting with surrounding molecular machinery to cause breakage and cellular dysfunction. It is significant enough in aging for the free radical theory of aging to have arisen some decades ago, postulating that oxidative damage was the cause of aging. Alas, matters are not that simple. Persistently raised levels of oxidative stress are a downstream consequence of deeper causes, such as mitochondrial dysfunction, chronic inflammation, cellular senescence, and the like. Further, oxidative molecules do in fact serve a necessary and useful role in healthy cellular metabolism. They act as signals to spur cellular maintenance, for example, and thus small or temporary increases in oxidative stress tend to be beneficial. This is one of the mechanisms by which exercise produces health benefits.

Naked mole rats are a strange species, an outlier among rodents. They are eusocial, like some insects. They live nine times longer than similarly sized rodent species, and show few signs of aging across most of that life span. They exhibit high levels of oxidative stress, but appear near completely immune to the consequences that would appear in rats or mice given the same flood of oxidative molecules. They show the presence of senescent cells, but appear largely unaffected by that as well, which is interesting given the very prominent role played by the harmful, inflammatory secretions of senescent cells in the aging and age-related diseases of mice. Finally, naked mole rats are near immune to cancer.

Needless to say, researchers are quite interested in learning how exactly of all this is possible. Might any of the findings result in biotechnologies that can be applied to humans, to shut down cancer, or resist aging? No-one knows. My suspicion is that it will take a while to find out, and there is a good chance that altering humans to be more like naked mole rats is not a near term project - something for the latter half of the century, not the next few decades. I would say we are better off trying to repair the metabolism we have rather than building a better one, given the present state of biotechnology. It is a much more plausible goal.

The Naked Mole Rat: A Unique Example of Positive Oxidative Stress

More than 60 years ago, it was first proposed that aging could be attributed to the deleterious effects of free radicals produced as natural by-products of aerobic metabolism. The free radical theory of aging (FRTA) is based on the hypothesis that dysfunctions observed during aging and a range of age-associated pathologies are due to the accumulation of oxidative damage to biological macromolecules (e.g., DNA damage, lipid peroxidation, and nonrepairable protein oxidation) by reactive oxygen and nitrogen species. A more precise version of the free radical theory of aging, called the mitochondrial free radical theory of aging (MFRTA), specifies that mitochondria are the main sources of reactive oxygen species (ROS) generation and are also the targets of deleterious effects: oxidative damages to mitochondrial DNA, mitochondrial proteins, or phospholipids are assumed to directly cause aging.

Naked mole rats (Heterocephalus glaber), first described in 1842, are the longest living rodents known. Several studies have investigated the production of free radicals and oxidative damages in the naked mole rat, and the results are puzzling. Despite remarkably long lives, some tissues of the naked mole rat, such as arteries, produce higher amounts of ROS (from cytoplasmic and mitochondrial sources) as compared to these tissues from the short-lived mouse. Importantly, the arteries of naked mole rats are highly resistant to the pro-apoptotic effects of ROS in vitro, whereas those of the mouse are not.

Furthermore, several studies have shown that naked mole rats have high levels of oxidative damages to macromolecules from a young age. Interestingly, these levels of damages are maintained over a 20-year period without increase. One hypothesis is that further damages are attenuated by an efficient repair system. A limit of these studies is that only damages to macromolecules were investigated: mitochondrial DNA damage has not been studied in naked mole rat tissues. Hence, further studies using this unique animal model are needed as it would be very informative to compare ROS-producing systems from cellular and mitochondrial sources and oxidative damage in nuclear, cytoplasmic, and mitochondrial targets in long-lived naked mole rat and short-lived rodents.

Many, but not all, features of the naked mole rat defy the free radical theories of aging. However, there is a recent extension of the theory, called the membrane pacemaker theory of aging, which holds true in the naked mole rat. This theory predicts that membrane fatty acid composition has an influence on lipid peroxidation and consequently may be an important determinant of aging and lifespan. Indeed, a study showed that naked mole rat membranes from different tissues contain more fatty acids resistant to peroxidation than do membranes from mice. Thus, the cellular membrane composition of the naked mole rat could partially explain their exceptional longevity. Still, the "naked mole rat exception" raises the question of whether or not ROS (cytoplasmic and mitochondrial) are responsible for aging.

Chronic inflammation and oxidative stress disrupt the function of smooth muscle cells in blood vessel walls. This is one of the contributing causes of vascular stiffness with age, alongside cross-links, calcification, and loss of elastin, all of which alter the structural properties of blood vessel tissue to produce a reduction in elasticity. There is the question of the relative importance of these contributions, a question that exists for most aspects of aging at the present time, lacking easy ways to remove only one contributing factor to assess the outcome. Nonetheless, the research results noted here suggest that smooth muscle dysfunction is the most important factor in vascular stiffness, and that - in mice, at least - changes in gut bacteria populations are the cause of this issue. This might make us more optimistic about the prospects for near term therapies in humans.

Stiffening of blood vessels is important because it results in hypertension; the feedback mechanisms controlling blood pressure are disrupted by this type of damage and dysfunction. That in turn produces tissue damage throughout the body due to rupture of capillaries and other pressure-related issues. Hypertension also accelerates the progression of atherosclerosis, and makes it more likely for fatal structural failures in large blood vessels to occur in the later stages of that condition.

Why do blood vessels naturally stiffen and degrade as we age, boosting cardiovascular disease risk? Researchers gave young mice and old mice broad-spectrum antibiotics to kill off the majority of bacteria living in their gut, aka their gut microbiome. Then they assessed the health of their vascular endothelium (the inner lining of their blood vessels) and the stiffness of their large arteries. They also measured blood levels of inflammatory compounds, tissue-damaging free-radicals, antioxidants, and the blood-vessel-expanding compound nitric oxide in both groups. After three to four weeks of the treatment, the young mice saw no change in vascular health. The old mice, however, saw vast improvements on all measures. "When you suppressed the microbiome of the old mice, their vascular health was restored to that of young mice. This suggests there is something about those microorganisms that is causing vascular dysfunction."

To assess what that something may be, the researchers then took fecal samples from another set of mice and had them genetically sequenced, comparing the gut bacteria living in the old mice with that in the young. In the old mice, the researchers saw an increased prevalence of microbes that are pro-inflammatory and have been previously associated with diseases. For instance, the old mice hosted significantly more Proteobacteria, a phyla that includes Salmonella and other pathogens, and pro-inflammatory Desulfovibrio. To drill down further, the researchers measured blood levels of metabolites - small molecules produced by the gut microorganisms and absorbed into the bloodstream - in old and young mice. Old mice had three times as much TMAO (trimethylamine N-oxide), a metabolite shown in previous studies to be linked to increased risk of atherosclerosis, heart attack, and stroke.

"We have long known that oxidative stress and inflammation are involved in making arteries unhealthy over time, but we didn't know why arteries begin to get inflamed and stressed. Something is triggering this. We now suspect that, with age, the gut microbiota begins producing toxic molecules, including TMAO, which get into the blood stream, cause inflammation and oxidative stress and damage tissue." The researchers recently launched a human trial to explore how different diets impact the gut and, in turn, cardiovascular disease risk. They are also studying a compound called dimethyl butanol, which blocks the bacterial enzyme required to produce TMAO. Ultimately, it could be developed into a dietary supplement.

Link: https://www.colorado.edu/today/2019/03/19/fountain-youth-heart-health-may-lie-gut

The science of intervention in aging has reached the point at which the research community should be undertaking a great deal more of the sort of work exhibited here. The authors of this open access paper have done the public service of producing reference data on telomere length and mitochondrial DNA copy number in multiple tissues over the mouse life span. Telomere length is a terrible metric for aging when measured in the immune cells taken from a blood sample; it varies widely between individuals, is dynamic for a given individual, dependent on day to day environmental and health factors, and trends with age only show up in statistical analyses carried out across sizable study populations - and sometimes not even then. Mitochondrial DNA copy number is more interesting, and a reference work here might be quite useful.

Both of these metrics, regardless of their quality or lack of same, are downstream consequences of lower-level forms of damage in aging. Average telomere length is a loose measure of stem cell activity, a proxy for the replacement rate for cells in a tissue. Stem cell activity declines with age, and thus so does the supply of new cells with long telomeres. Mitochondrial DNA copy number is generally thought to fall with age (though see the results below), and lower copy number counts correlate with poor health outcomes. Mitochondria, the power plants of the cell, undergo a general malaise with age, their function faltering, and this contributes to many age-related conditions, particularly in energy-hungry tissues like muscles and the brain. These processes have underlying causes, and go on to cause further issues themselves. A good fraction of the research community involved in aging seeks to override these evident declines without trying to address the root causes - an approach that may well produce some benefits, but will not solve the problem of aging in and of itself.

Our study aimed to provide chronological aging standard curves and slopes of telomere length and mitochondrial DNA copy number (mtDNAcn), which can help researchers objectively assess the degree of aging in target tissues in various studies using C57BL/6 male mice. C57BL/6 is one of the commonly used rodent models. To evaluate telomere length by qPCR, we used the telomere primer set telg and telc. Unlike previously suggested primers that generate PCR products of various lengths, the telg and telc set produced PCR products of constant length, resulting in stable amplification and clear chronological standard curves.

The telomere qPCR conditions proposed in this study resulted in reproducible and discriminating amplification outcomes, and the fidelity of the qPCR result was further confirmed by telomere restriction fragment (TRF) analysis. The telomere standard curves also showed significant changes with aging. To the best of our knowledge, this is the first report of the aging standard curves of mouse telomeres using the telg and telc set and integrating various tissues across the body.

All 12 tissues showed age-dependent changes in telomere length or mtDNAcn, indicating that we can estimate tissue-specific aging status using at least one of these aging markers. A variety of studies have indicated that telomere erosion occurs in aged human or animal subjects. In our study, all tissues showed telomere length decline with aging. However, the mtDNAcn showed a tendency to increase or decrease with aging depending on the tissue. We found increments in mtDNAcn in the retina, thoracic aorta, and spleen, but the other tissues showed a decreasing tendency with aging.

In addition to mitochondrial dysfunction due to a decreased mitochondrial genome, increased mtDNAcn has also been suggested to be detrimental to cells and eventually induces cellular senescence or apoptosis. Accumulation of mtDNA mutations induces high mtDNAcn in nucleoids (mtDNA-protein complexes), and results in nucleoid enlargement and subsequent mitochondria functional deficiency. Excessive mtDNA replication could be triggered by the activation of twinkle mtDNA helicase and mitochondrial transcription factor A. These previous studies support the notion that an increase in mtDNAcn is a normal phenomenon in aging, although the mechanism of tissue-specific increase or decrease with aging remains to be elucidated.

It is known that telomerase activity in adult tissues differs between human and rodents. Telomerase is constitutively expressed in various tissues of laboratory mice, whereas it is tightly regulated in human somatic cells. Therefore, the results of mouse experiments cannot be directly applied to humans. Nevertheless, animal model experiments are indispensable to understanding human diseases, and the results have to be compared with human data to infer the clinical symptoms of the human body.

Link: https://doi.org/10.3390/cells8030247

In recent years researchers have investigated changes in alternative splicing in the context of aging and age-related disease. It is thought to be important in cellular senescence, for example, but that is just one line item in the bigger picture. A given gene can code for multiple different proteins, and alternative splicing is the name given to the processes by which those different proteins are produced. A gene contains discrete DNA sequences called exons and introns, the former passed into the protein production process, and the latter removed during RNA splicing. The canonical protein produced from this genetic blueprint contains all of the exons, joined in sequence, but alternative splicing may drop exons, resulting in a different protein.

The balance between the proteins produced from a given gene tends to shift with age. This might be a harmful downstream consequence of underlying molecular damage, or an evolved reaction to attempt to compensate for that damage in some way. All too little mapping of these age-related changes in alternative splicing has been carried out, but we might regard it as yet another form of gene expression regulation, akin to epigenetic changes that alter the pace of production of proteins.

Intron retention is another possible form of alternative splicing. Instead of an intron being removed, it is included in the process of producing a protein. This also results in a different protein with different characteristics. In today's open access paper, researchers look specifically at intron retention in flies, mice, and humans, finding that rates of this phenomenon correlate with age and neurodegenerative disease. The water is muddied somewhat by the point that this alternative splicing does take place to some degree in young individuals, as a normal part of the operation of cellular metabolism. Nonetheless, it seems likely that someone might produce an intron retention clock analogous to the epigenetic clocks presently demonstrated to measure age quite well.

Alternative splicing is a regulatory mechanism that generates multiple mRNA transcripts from a single gene. While this process is essential for many biological processes such as neurogenesis, alteration in the splicing patterns is also prevalent during aging and may contribute to many age-onset diseases like Alzheimer's disease (AD). Intron retention (IR) occurs when a specific intron remains unspliced in the mature polyadenylated mRNA. As an IR may trigger nonsense-mediated decay (NMD) of mRNA or introduce mutation in the translated protein, it has been widely considered as an aberrant splicing event that is associated with various diseases.

For instance, dysregulated IR is one of the drivers of transcriptome diversity in cancer and can lead to inactivation of different tumor-suppressor genes. IR in endoglin and EAAT2 gene also leads to cellular senescence and amyotrophic lateral sclerosis, respectively. Interestingly, dietary restriction in worms could reduce aberrant IR caused by defective splicing during aging, suggesting that IR at specific genes can be used as disease biomarkers or targets for therapeutic intervention. Accumulated evidence indicated that IR may also play an important regulatory role during normal development, including translational inhibition in response to hypoxic stress, regulation of mRNA expression patterns during hematopoiesis and neurogenesis. Therefore, defining age-associated changes to IR may allow a far better understanding into how IR may regulate the transition from healthy to the pathological state during aging.

To this end, we analyzed the in-house RNA-sequencing data of aging male Drosophila heads and observed a global increase in the level of IR as the animals aged. Interestingly, IR affects functionally distinct groups of genes at different stages of an adult lifespan. Consistent with the role of chromatin structure in regulating RNA splicing, we found that nucleosome positioning within a subset of introns in young flies correlated with their differential retention in older animals. Further analyses of transcriptome from mouse and human brain tissues suggest that the global increase in IR during aging may be evolutionarily conserved. The differentially retained introns identified from different species share several similar characteristics, including shorter length when compared to spliced introns and not susceptible to NMD.

Notably, several differential IR genes identified from aging Drosophila and human brain tissues are linked to AD-related pathways, postulating that the pattern of IR may undergo further changes during AD progression. To test this possibility, we analyzed AD datasets from the cerebellum and frontal cortex, and observed a global increase in the level of IR in AD brain tissues when compared to the control samples. These differentially retained introns have a shorter length and higher GC content compared to the spliced introns. Differential IR genes are enriched for functions associated with RNA processing and protein homeostasis, with more than a hundred of them having an altered level of protein expression in AD frontal cortex. Taken together, our results suggest that a global increase in IR may be a transcriptional signature of aging that is conserved across species and differential IR at specific genes may contribute to the etiology of late-onset sporadic AD.

Link: https://doi.org/10.1111/acel.12928

Researchers here show that it is the chronic inflammation of aging that is the dominant contributing cause of loss of capacity in bone regeneration in later life. We should all feel a degree of relief whenever it turns out that chronic inflammation is the primary proximate cause of an age-related condition. Age-related inflammation is driven by senescent cells and immune system failure. Therapies to remove senescence cells are well advanced in clinical development, and there are many potential lines of work that will lead to ways to reverse the dysfunction of the aged immune system in years to come. The inflammatory profile of an old individual twenty years from now will look very different from the inflammatory profile of an old individual today.

A new study finds that increases in chronic inflammation - not the passage of time - is the main reason why injured bones do not heal as well with age. The results revolve around the known breakdown, due to wear and tear, of the protein machines and large molecules necessary for the life of human cells, the remnants of which trigger the immune system. First studied in its role in destroying invading microbes, this system also can react to the body's own proteins to cause inflammation, a response that fights infection at the site of injury and transitions into the healing process. The current study explains how this age-driven increase in immune signals diminishes the ability of stem cells - essential ingredients in bone repair - to multiply

The current study is based on the observation in human patients that stem cell number in the bone marrow significantly declines with increasing age, and that fractures take longer to heal as the stem cell number drops. The research team then moved to mouse models to explore the related mechanisms. The researchers found that exposing stem cells from young mice to the blood serum of the older mice made their stem cells four times less likely to divide and multiply, an irreversible state called senescence. Past studies had also shown that senescent stem cells send signals that encourage inflammation in a vicious circle.

Furthermore, treatment over time with sodium salicylate, an ingredient in aspirin, repressed NFκB signals and related aged-induced chronic inflammation, increasing the number and bone-healing contribution of skeletal stem cells. Further experiments revealed that anti-inflammatory treatment changed the action of thousands of genes in the stem cells, restoring them to a genetic profile seen in young skeletal stem cells. These results suggest that it is inflammation, not chronological age, that hinders bone healing in the elderly.

An obstacle to the translation of the findings into future treatments is that rejuvenating bone stem cells with anti-inflammatory drugs just after a bone fracture would also block the acute inflammation that is necessary for successful bone healing. This suggests that a more immediate application may be to use anti-inflammatory drugs to build up stem cell pools, not after bone breaks, but during the weeks before elective orthopedic surgeries like hip or knee replacements. In these cases, anti-inflammatory drugs would be used leading up to a surgery, but then be cut off just before to make way for the acute inflammation necessary to normal healing.

Link: https://www.eurekalert.org/pub_releases/2019-03/nlh-cl031319.php

Hypertension, raised blood pressure due to age-related dysfunction of blood vessels, is an important process in aging. It is one of the more important ways in which low-level biochemical damage and cellular malfunctioning is converted into high level structural damage to tissues. Pressure damage to the sensitive tissues of the brain, kidney, lungs, and more causes large degrees of functional loss when taking place over years. In the brain, rupture of capillaries leads to countless tiny, unnoticed strokes, each destroying a small volume of brain tissue. This slowly adds up to produce cognitive decline and dementia, one small loss at a time.

Elderly people with high blood pressure, or hypertension, who took medicine to keep their 24-hour systolic blood pressure around 130 mm Hg for three years showed significantly less accumulation of harmful brain lesions compared with those taking medicine to maintain a systolic blood pressure around 145 mm Hg, according to new research. However, the reduction in brain lesions, visible as bright white spots on a magnetic resonance imaging (MRI) scan, did not translate to a significant improvement in mobility and cognitive function. Researchers said it is likely that three years was too short a time for such benefits to become apparent.

The study, called INFINITY, is the first to demonstrate an effective way to slow the progression of cerebrovascular disease, a condition common in older adults that restricts the flow of blood to the brain. The study is also unique in its use of around-the-clock ambulatory blood pressure monitors, which measured participants' blood pressure during all activities of daily living, rather than only in the medical care environment. In addition to seeing beneficial effects in the brain, those who kept their blood pressure lower also were less likely to suffer major cardiovascular events, such as a heart attack or stroke.

"I think it's an important clinical finding, and a very hopeful one for elderly people who have vascular disease of the brain and hypertension. With the intensive 24-hour blood pressure treatment we reduced the accrual of this brain damage by 40 percent in a period of just three years. That is highly clinically significant, and I think over a longer time period intensive reduction of the ambulatory blood pressure will have a substantial impact on function in older persons, as well."

Link: https://www.acc.org/about-acc/press-releases/2019/03/17/22/15/lowering-blood-pressure-prevents-worsening-brain-damage-in-elderly

Cellular senescence is an important contributing cause of aging. Senescent cells accumulate with age and secrete a potent mix of molecules and vesicles, the senescence associated secretory phenotype. This disrupts tissue function in a range of ways, and produces chronic inflammation that accelerates the progression of all of the common age-related conditions. All forms of cell in the body appear to be capable of senescence, and the cells of the immune system are no exception. With advancing age, an increasing number of T cells of the adaptive immune system become senescent, producing the same damaging secretions.

Exactly what damage is done by senescent T cells? Firstly, it appears that they contribute to autoimmunity - which is very interesting in light of other work showing that senescent cells of other varieties also contribute to the autoimmune condition of type 1 diabetes. Secondly, senescent T cells, like other senescent cells, produce the outcome of chronic inflammation in tissues throughout the body. The harms done by inflammation sustained over the long term really can't be overstated: it degrades function and accelerates most of the aspects of degenerative aging.

Researchers here find that, interestingly, senescent T cells appear to be quite influential in the pathology of type 2 diabetes. This is near entirely a self-inflicted condition produced by the presence of excess visceral fat tissue and its distorting effect on metabolism. Type 2 diabetes appears to also result in larger numbers of senescent T cells - which fits with other evidence suggesting that the pathway of obesity, metabolic syndrome, and type 2 diabetes tends to produce more senescent cells in general, particularly in fat tissue, and leads to a shorter life expectancy and earlier onset of age-related disease.

T-cell senescence contributes to abnormal glucose homeostasis in humans and mice

Chronic inflammation is strongly associated with metabolic diseases, including diabetes and atherosclerosis. Patients with insulin resistance are considered to be at greater risk of cardiovascular disease. Proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, play essential roles in the pathogenesis of insulin resistance. Moreover, patients with prediabetes show significantly lower insulin sensitivity and higher levels of inflammatory markers than metabolically normal individuals. In addition, low-grade inflammation in prediabetes is thought to increase the risk of a cardiovascular event.

Aging of the immune system also contributes to the development of chronic inflammation and has an important effect on metabolic disease and immunologic disorders in humans. In addition, low-grade chronic inflammation is a driver of immunosenescence. The chronic inflammatory environment that is a characteristic of metabolic diseases may also be induced by augmented secretion of proinflammatory cytokines, including TNF-α and IL-6, reactive oxygen species (ROS), and acute-phase reactants released from senescent immune cells. In human studies, several lines of evidence indicate that a senescent T-cell-mediated inflammatory response is associated with the pathogenesis of acute coronary syndrome and hypertension. However, any relationship between the immunosenescence of T cells and abnormal glucose homeostasis remains to be elucidated.

In the present study, we investigate whether T-cell senescence contributes to the systemic inflammatory response in patients with prediabetes and mice with diet-induced obesity by immunologically characterizing senescent T cells. We studied the patients visiting a hospital for routine health check-ups, who were divided into two groups: normal controls and people with prediabetes. Gene expression profiling of peripheral blood mononuclear cells from normal controls and patients with type 2 diabetes was undertaken using microarray analysis. We also investigated the immunometabolic characteristics of peripheral and hepatic senescent T cells in the normal subjects and patients with prediabetes. Moreover, murine senescent T cells were tested functionally in the liver of normal or mice with metabolic deterioration caused by diet-induced obesity.

Human senescent (CD28-CD57+) CD8+ T cells are increased in the development of diabetes and proinflammatory cytokines and cytotoxic molecules are highly expressed in senescent T cells from patients with prediabetes. Moreover, we demonstrate that patients with prediabetes have higher concentrations of reactive oxygen species (ROS) in their senescent CD8+ T cells via enhancing capacity to use glycolysis. These functional properties of senescent CD8+ T cells contribute to the impairment of hepatic insulin sensitivity in humans.

Furthermore, we found an increase of hepatic senescent T cells in mouse models of aging and diet-induced obesity. Adoptive transfer of senescent CD8+ T cells also led to a significant deterioration in systemic abnormal glucose homeostasis, which is improved by ROS scavengers in mice. This study defines a new clinically relevant concept of T-cell senescence-mediated inflammatory responses in the pathophysiology of abnormal glucose homeostasis. We also found that T-cell senescence is associated with systemic inflammation and alters hepatic glucose homeostasis. The rational modulation of T-cell senescence would be a promising avenue for the treatment or prevention of diabetes.

The adaptive immune system consists of many different types of cell, undertaking many different tasks, all falling into the two broad categories of T cells and B cells. With age, the immune system falls into a chronic state of inflammation and overactivation (inflammaging) at the same time as it becomes ever less capable of defending tissues against pathogens and rogue cells (immunosenescence). Researchers have identified numerous potentially harmful subpopulations of both T and B cells in the aged immune system, and in the case of B cells have even selectively removed and replaced them, a procedure that resulted in improved immune function in mice.

That demonstration in mice was accomplished nearly a decade ago, and it is disappointing that comparatively little progress towards the clinical application of this sort of approach to immune aging has occurred since then. The evidence, from many animal studies and the few human trials of immune cell clearance undertaken, clearly shows that removing and replacing the immune system is beneficial because it destroys problem populations of immune cells. The challenge lies in producing a method of clearance that has few risks and side-effects, but the component parts of that technology certainly already exist - just look at Oisin Biotechnologies' target cell destruction platform for example.

Humoral immune responses mediated by B cells are important for adaptive immunity. B cells produce a diverse set of antibodies, which help in effectively eliminating antigens including pathogens. In addition, B cells play an indispensable role in the immune system via presentation of antigens and secretion of cytokines. In aged individuals, a spectrum of immune system alterations, termed "immune senescence," result in a blunted adaptive immune response, an increased tendency for inflammatory responses, enhanced susceptibility to infections, and an increased production of autoantibodies. Multiple factors may contribute to these immune activity changes. T cells have been shown to participate in immune senescence. However, the role of B cells in this respect remains unclear.

Recent findings illustrate conspicuous shifts in B cell subsets in the elderly, suggesting that age-related changes in B cells may contribute to immune senescence. The discovery of a subset of B cells that express T-bet, termed age-associated B cells (ABCs), has drawn significant attention in recent years. Initially isolated from aged donors and found to be closely associated with immune senescence, these cells were expected to provide a novel therapeutic avenue for autoimmune diseases.

These B cells first accumulated in the spleen and increased significantly in the bone marrow with age. ABC phenotypes are distinct from other B cell subsets. ABCs expressed similar levels of IgM and lower levels of IgD compared to follicular B cells. In addition, cell cycle analyses showed that ABCs were quiescent, suggesting that they are not a subset of self-renewing cells. Because ABCs were explored using mouse models, the existence of similar cells in aged humans may need confirmation. More interestingly, B cells with phenotypes similar to that of ABCs appear in both mice and humans, during the course of certain autoimmune diseases, and following some viral infections.

ABCs responded only to TLR7 and TLR9 stimuli in vitro. They were found to secrete antibodies upon TLR stimulation rather than upon BCR stimulation. Since TLRs are commonly associated with skewing toward inflammatory responses, increased numbers of ABCs may yield more innate immune responses, characterized by low-affinity antibody, and inflammatory processes. Furthermore, ABCs directly participate in producing autoantibodies, indicating that they are associated with serious autoimmunity seen in the aged. Considered together, ABCs appear to play multiple roles in age-associated alteration of immune activity. However, antigen-presentation ability is mainly displayed in in vitro assays. Interaction of ABCs with the other immune cells in vivo may need further exploration.

Link: https://doi.org/10.3389/fimmu.2019.00318

One of the more interesting findings in the epidemiology of exercise, enabled by the development of lightweight accelerometers to measure daily activity, is that even very modest levels of movement and exertion have a significant correlation with health outcomes in later life. People who cook, walk a little, and tinker in the garden have meaningfully lower mortality rates than those who do not, and the effect scales through different degrees of this sort of low-level exercise. The important question to ask here is whether or not physical activity causes health benefits. The alternative explanation is that people who are healthier and more robust naturally tend to be more active. Human data usually doesn't allow for any inspection of causation, as opposed to the discovery of correlations, but animal studies have definitively shown that exercise causes improved health - although it doesn't appear to extend overall life span to any meaningful degree.

Despite impressive declines in age-standardized coronary heart disease (CHD) mortality rates since the 1960s, cardiovascular disease (CVD) remains the leading cause of death in the United States and globally. More than half a million older American individuals die of CVD annually. Physical activity (PA) is a key candidate for reducing CHD risk in older women. The long-standing, prevailing paradigm in PA research is that moderate to vigorous PA (MVPA) for at least 150 minutes per week is needed to prevent CVD in adults. However, a meta-analysis of 9 epidemiologic studies found reduced risks of CHD associated with levels of self-reported MVPA (≥3 metabolic equivalent tasks [METs]) that were lower than the recommended guidelines.

Light PA at intensity levels of 1.5 to 3.0 METs is poorly measured by self-reported questionnaires because they fail to capture light movements performed habitually throughout the day. Recent reports reveal that light PA measured by accelerometry is associated with reduced risks of total and CVD mortality, as well as favorable levels of CVD risk factors. In this prospective cohort study of older women, light PA measured by accelerometry was associated with a dose-responsive, independent reduced risk of incident CHD and CVD events. The highest quartile of light PA was associated with a 42% reduced risk of myocardial infarction or coronary death and a 22% reduced risk of incident CVD events compared with the lowest quartile of light PA. These reduced risks persisted after multivariable adjustment that included physical functioning and other measures of health status, even though some covariates may themselves be altered by PA and thus dilute the associations.

Link: https://doi.org/10.1001/jamanetworkopen.2019.0419

Turn.bio is Gary Hudson's latest company, now that others are running the day to day development at Oisin Biotechnologies. The Turn.bio staff are working on a particular take on the idea of inducing pluripotence in cells in vivo as a form of compensatory therapy for aging. This is a concept that struck me as being fairly crazy the first time I saw it discussed in a research publication. It is certainly possible to reliably reprogram somatic cells of near any sort into what are known as induced pluripotent stem cells, capable of differentiating into any type of cell. This is the foundation for the production of arbitrary cell types for transplantation. But doing it inside a living animal? Surely a recipe for cancer and more cancer, as the pluripotent cells replicate uncontrollably outside the normal restraints of a structured tissue.

Oddly, however, the initial outcome in mice was not cancer and more cancer. It was a set of benefits to health and tissue function that looked a lot like the results of stem cell therapies, most likely achieved via the signaling produced by the newly induced pluripotent stem cells. It remains to be seen what the risks look like over the long term, but the result prompted some interest and following studies in the research community. Given this, what if it were possible to guide cells only part-way into a pluripotent state, and only temporarily, generating beneficial signals for a time without any meaningful risk of pluripotent cells floating around in tissues for the long term? That is what the Turn.bio staff are working on. The result may be a more controllable, guided way to achieve the benefits of stem cell therapy without the stem cells. The paper here is the basis for their current development program.

Transient non-integrative nuclear reprogramming promotes multifaceted reversal of aging in human cells

The process of nuclear reprogramming to induced pluripotent Stem cells (iPSCs) is characterized, upon completion, by the resetting of the epigenetic landscape of cells of origin, resulting in reversion of both cellular identity and age to an embryonic-like state. Notably, if the expression of the reprogramming factors is applied only for a short time and then stopped - before the so-called Point of No Return (PNR) - the cells return to the initiating somatic cell state. These observations suggest that if applied for a short enough time (transient reprogramming), the expression of reprogramming factors fails to erase the epigenetic signature defining cell identity; however, it remains unclear whether any substantial and measurable reprogramming of cellular age can be achieved before the PNR and if this can result in any amelioration of cellular function and physiology. To test this, we first evaluated the effect of transient reprogramming on the transcriptome of two distinct cell types - fibroblasts and endothelial cells - from aged human subjects, and we compared it with the transcriptome of the same cell types isolated from young donors.

We utilized a non-integrative reprogramming protocol that we optimized, based on a cocktail of mRNAs expressing OCT4, SOX2, KLF4, c-MYC, LIN28 and NANOG (OSKMLN). Our protocol consistently produces induced pluripotent stem cell (iPSC) colonies, regardless of age of the donors, after 12-15 daily transfections; we reasoned that the PNR in our platform occurs at about day 5 of reprogramming, based on the observation that the first detectable expression of endogenous pluripotency-associated lncRNAs occurs at day 5. Therefore, we adopted a transient reprogramming protocol where OSKMLN were daily transfected for four consecutive days, and performed gene expression analysis two days after the interruption.

Analysis of transcriptomic signatures revealed that transient reprogramming triggers a more youthful gene expression profile, while retaining cell identity. Epigenetic clocks based on DNA methylation levels are the most accurate molecular biomarkers of age across tissues and cell types and are predictive of a host of age-related conditions including lifespan. Exogenous expression of canonical reprogramming factors (OSKM) is known to revert the epigenetic age of primary cells to a prenatal state. To test whether transient expression of OSKMLN could reverse the epigenetic clock, we used two epigenetic clocks that apply to human fibroblasts and endothelial cells: Horvath's original pan-tissue epigenetic clock, and the more recent skin and blood clock. According to the pan-tissue epigenetic clock, transient OSKMLN significantly reverted the DNA methylation age.

This data demonstrates that transient expression of OSKMLN can induce a rapid, persistent reversal of cellular age in human cells at the transcriptomic, epigenetic, and cellular levels . Importantly, these data demonstrate that the process of "cellular rejuvenation" - that we name Epigenetic Reprogramming of Aging, or "ERA" - is engaged very early and rapidly in the iPSC reprogramming process. These epigenetic and transcriptional changes occur before any epigenetic reprogramming of cellular identity takes place, a novel finding in the field.

Sarcopenia is an age-related condition that is characterized by loss of muscle mass and force production. We wanted to test whether transient reprogramming of aged muscle stem cells (MuSCs) would improve a cell-based treatment in restoring physiological functions of muscle of older mice. To test this, we first performed electrophysiology to measure tetanic force production in tibialis anterior (TA) muscles isolated from young (4 months) or aged (27 months) immunocompromised mice. We found that TA muscles from aged mice have lower tetanic forces compared to young mice, suggesting an age-related loss of force production. Next, we isolated MuSCs from aged mice (20-24 months). After treating aged MuSCs, we transplanted them into injured TA muscles of aged (27 months) immunocompromised mice. We waited 30 days to give enough time to the transplanted muscles to fully regenerate. We then performed electrophysiology to measure tetanic force production.

Muscles transplanted with untreated aged MuSCs showed forces comparable to untransplanted muscles from aged control mice. Conversely, muscles that received treated aged MuSCs showed tetanic forces comparable to untransplanted muscles from young control mice. These results suggest that transient reprogramming in combination with MuSC-based therapy can restore physiological function of aged muscles to that of youthful muscles.

Periodontitis is the later stage of gum disease, an inflammatory condition largely caused by particular strains of bacteria found in the mouth. While there is a fair amount of promising work related to destroying or sabotaging the disease-causing mechanisms of those bacterial species, nothing has yet made the leap to earnest clinical development. It is thought, based on epidemiological data showing an association with mortality, and on a reasonable examination of the mechanisms involved, that periodontitis can spread inflammatory signaling elsewhere in the body, particularly to the heart and the brain, and thereby accelerate the progession of age-related conditions. The research here, however, using study data for a large number of patients, shows only a modest effect on the incidence of dementia due to the presence of periodontitis.

Gum disease (gingivitis) that goes untreated can become periodontitis. When this happens, the infection that affected your gums causes loss in the bone that supports your teeth. Periodontitis is the main cause of tooth loss in adults. Interestingly, periodontitis is also a risk factor for developing dementia, one of the leading causes for disability in older adults. Recently, researchers in South Korea studied the connection between chronic periodontitis and dementia. The research team examined information from the National Health Insurance Service-Health Screening Cohort (NHIS-HEALS). In South Korea, the NHIS provides mandatory health insurance covering nearly all forms of health care for all Korean citizens. The agency also provides health screening examinations twice a year for all enrollees aged 40 years or older and maintains detailed health records for all enrollees.

The researchers looked at health information from 262,349 people aged 50 or older. All of the participants were grouped either as being healthy (meaning they had no chronic periodontitis) or as having been diagnosed with chronic periodontitis. The researchers followed the participants from January 1, 2005 until they were diagnosed with dementia, died, or until the end of December 2015, whichever came first. The researchers learned that people with chronic periodontitis had a 6 percent higher risk for dementia than did people without periodontitis. This connection was true despite behaviors such as smoking, consuming alcohol, and remaining physically active.

Link: https://www.healthinaging.org/blog/periodontitis-may-raise-the-risk-for-developing-dementia/

The Academy for Health and Lifespan Research was recently announced, an initiative analogous to that of the long-running Longevity Dividend group, but hopefully more energetic and more focused on at least some rejuvenation biotechnologies such as senolytic therapies. The principals include many of the researchers now involved in startup biotech companies working on ways to intervene in the mechanisms of aging, and the goal is to generate greater support for development of means to slow or reverse aging and age-related disease. David Sinclair is associated with Life Biosciences and its collection of portfolio companies, and here discusses the Academy and its future role.

Tell me about the academy. Is it intended to be mainly an advocacy organization?

The academy has been formed because our field of aging and longevity research has reached a point of maturity where the leaders in the field believe that we can have - or will have - a big impact on the planet. That impact will be in medicine, in health span, and in its knock-on effect on everything from human productivity to Social Security. We wanted to come together to speak with one voice, to be able to help corporations and governments understand what things they should be thinking about now and give realistic projections of what life is going to be like 10, 20, 50 years from now. Because it's not a question of if there's going to be an impact, it's really a question of what kind of a future we want to build when this happens.

What kind of impact are we talking about? When you think about 10, 20, 50 years in the future, how do you see aging being transformed in the U.S. and around the world?

By impact, I mean that instead of tackling one disease at a time, which is the way 20th-century medicine and pharmaceutical development was practiced, we believe we can develop medicines that will treat aging at its source and thereby have a much greater impact on health and lifespan than drugs that target a single disease. Heart disease medicine may keep your heart healthy for an extra five or 10 years, but does nothing for your brain. So, we're ending up with a population of people who live longer but not better and who need a lot of help, if they're not completely in the grip of dementia. We don't think that's necessarily the only or the best approach.

Now, we have the knowledge. We're developing the technologies to not just delay these diseases of aging but actually reverse aspects of them. Imagine you have a treatment for heart disease, but as a side effect you'd also be protected against Alzheimer's, cancer, and frailty. You'd live a longer and healthier life. The reason we can extend the lifespan of animals is not because we can just make them live longer, but we keep them healthy. The animals don't get heart disease, cancer, Alzheimer's, until sometimes 20 percent later in their life. And so that's 20 percent longer youth, not just 20 percent longer life.

Are there regulatory hurdles? When we've spoken in the past, you've mentioned that the FDA considers aging a natural process and therefore won't approve drugs to treat it.

Opinions are changing rapidly about whether aging should be a condition that a doctor can prescribe a medicine for. We currently live in a world where aging is so common that it's considered by most of the world, including the medical community, as something that's natural and inevitable. And if something's considered inevitable, typically you don't focus on it in the same way as something you can treat. Cancer was a natural part of life at one time, in the same way that aging is today. A hundred years ago, doctors didn't focus on treating cancer as much as we do now, because then you couldn't do much, if anything, about it.

There are now dozens of companies working on therapies that could potentially extend overall human health and lifespan, but none of them are working specifically toward an approval for aging because the FDA wouldn't even know where to start. But that may be changing quickly. I've been part of a group that talked with the FDA, and they are willing and also quite enthusiastic about considering a change that defines aging as a disease. They would like us, first, to show that it's possible to change the rate of aging, which in my view is backward, but that's what they want. In Australia, the government is 100 percent behind this, at the FDA level and in the Ministry for Health. I'm hopeful that one country in the world - it may be Australia, it may be the U.S., it may be an Asian country - will change its definition of aging. Once one country changes its definition, then it will be a domino effect and the others will follow.

Link: https://news.harvard.edu/gazette/story/2019/03/anti-aging-research-prime-time-for-an-impact-on-the-globe/

Raised blood pressure with age, hypertension, is a major downstream consequence of low-level biochemical damage and cellular dysfunction, converting it into high-level structural damage in the body and brain. Hypertension is an important proximate contributing cause of ultimately fatal age-related conditions of the cardiovascular system, kidneys, brain, and lungs, among others. Pressure damage in delicate tissues degrades function in many organs, particularly in the central nervous system where there is little to no regeneration capable of reversing that damage. More subtly, hypertension also causes heart muscles to enlarge and weaken, contributing to heart failure. Hypertension also accelerates the development of atherosclerosis, through mechanisms independent of other factors such as chronic inflammation.

Hypertension is so great a contribution to age-related disease, such an important mediating mechanism, that it is possible to produce sizable reductions in mortality by forcing a lower blood pressure, even without addressing the underlying causes in any way. The widespread use of antihypertensive medications to achieve this goal is one of the success stories of mainstream medicine in recent decades. There are, sadly, not all that many mechanisms that rise to this level of importance as single downstream consequences of low-level biochemical damage in aging. Chronic inflammation is another, but beyond that the only way to make significant progress towards control of aging is to repair the underlying damage. Attempting to address downstream consequences is largely very hard and of limited utility. Control of blood pressure and inflammation are outliers in this context.

Sustained blood pressure control and coronary heart disease, stroke, heart failure, and mortality: An observational analysis of ALLHAT

Treatment and control of high blood pressure (BP) is a key strategy for reducing coronary heart disease (CHD), stroke, heart failure (HF), and all-cause mortality among adults with hypertension. Accordingly, clinical practice guidelines provide recommendations for accurately identifying adults with hypertension, initiating appropriate antihypertensive therapy, and achieving predefined BP goals that have been shown to be associated with lower cardiovascular disease (CVD) and all-cause mortality event rates in randomized trials. However, less is known about the role of sustaining BP control over time.

In clinical practice, patients may be followed over many years and often experience times of controlled as well as uncontrolled BP. There are several reasons why BP control may change over time, including changes in patients' health status or medication adherence, variability in BP measurement from visit to visit, or reduction in antihypertensive medication intensity due to concerns about overtreatment on the part of the provider. The proportion of visits at which patients achieve BP control can easily be calculated, could be used to facilitate discussions with patients about treatments goals, and could be used as a performance measure for quality improvement. Also, data on the effects of maintaining sustained BP control could be used to support greater treatment consistency over time or conversely, to allow higher BP levels at some visits.

Findings from a limited number of studies suggest that having BP control at a greater proportion of visits over time is associated with a lower CVD risk. However, prior studies included primarily white participants, those with existing coronary heart disease (CHD), or with multiple CVD risk factors. The purpose of the current study was to determine the association of sustained BP control with CHD, stroke, HF, and mortality in an observational analysis of a demographically and clinically diverse population within a large clinical trial, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Participation was restricted to 24,309 participants with four to seven visits with systolic BP (SBP) measurements during a 22-month period. Participants were as having sustained BP control (SBP lower than 140 mm Hg) at 100%, 75% to 100%, 50% to 75%, and fewer than 50% of visits during this period.

In this observational analysis of participants from ALLHAT, those with SBP control, defined as SBP lower than 140 mm Hg at fewer than 50% of study visits, were more likely to have a stroke, develop HF, or experience the combined outcome of fatal CHD/nonfatal myocardial infarction, stroke, or HF. These associations were present after adjustment for potential confounders. Compared to those with SBP control at 100% visits, adjusted hazard rations among those with SBP control at fewer than 50% of visits was 1.16 for fatal CHD/nonfatal myocardial infarction, 1.71 for stroke, 1.63 for heart failure, 1.39 for the composite CVD outcome, and 1.14 for mortality. Sustained SBP control may be beneficial for preventing stroke, heart failure, and CVD outcomes in adults taking antihypertensive medication.