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  • A Potentially Safe Mitochondrial Uncoupling Drug Candidate
  • Molecular Changes in the Lens of the Eye as a Potential Biomarker of Biological Age
  • An Example to Illustrate Why Navitoclax is Not a Suitable Clinical Senolytic Drug
  • Fitting Senescent Cells into a Modified Amyloid Cascade Hypothesis of Alzheimer’s Disease
  • Senescent Cardiomyocytes in Cardiovascular Disease
  • Blood Drainage from the Brain Slows with Age, Leading to Ventriculomegaly
  • Loss of Visual Acuity Correlates with Dementia Risk
  • Quantifying Loss of Kidney Function with Age in a Human Population
  • Threonine Restriction Promotes Health in Mice
  • Retraining the Immune System to Turn Off Autoimmunity
  • Blood Pressure Control Increases Life Expectancy Even in the Most Frail Elderly People
  • Repetitive Elements as a Transcriptomic Biomarker of Aging
  • Stiffening of the Extracellular Matrix Contributes to Age-Related Muscle Impairment
  • Regular Physical Activity Reverses Frailty in the Old
  • CD9 Expression in Cellular Senescence and Atherosclerosis

A Potentially Safe Mitochondrial Uncoupling Drug Candidate

Mitochondrial uncoupling is the mechanism by which cells generate heat. Mitochondria are the power plants of the cell, a herd of bacteria-like structures that conduct energetic processes to generate the chemical energy store molecule adenosine triphosphate (ATP). ATP is used to power all of the vital biochemical machinery of a cell. Mitochondrial uncoupling is a regulatory mechanism that changes the operation of a mitochondrion such that the energy it accumulates is dissipated as heat rather than powering the chemical reactions needed to generate ATP. This uncoupling is how mammals regulate body temperature.

Raised levels of mitochondrial uncoupling can produce useful outcomes to health over the long term. It can be protective of tissues by reducing the degree to which mitochondria generate oxidative molecules. Unfortunately, this class of intervention so far doesn’t appear to increase life span, despite tending to reduce excess visceral fat tissue, a significant contributing cause of age-related disease. The practice of calorie restriction does increase mitochondrial uncoupling, but it is unclear as to the degree to which this is important to the outcome of improved health and longevity that occurs in calorie restricted animals.

Nonetheless, there has been some effort over the years to produce drugs that can increase mitochondrial uncoupling. The primary objection to the use of such compounds in the clinic is that, historically, they have not been all that safe. They increase uncoupling in a dose-dependent manner, but increasing uncoupling to a sizable degree can result in severe trauma or death due to excess heat generation. The distance between a useful dose and a lethal dose just isn’t large enough for comfort. DNP is a good example of such a compound, one with the added safety concern of being explosive. There are signs of progress, however. Researchers here report on a mitochondrial uncoupling drug candidate that appears to be useful at reasonable doses and, more importantly, safe at high doses.

Drug researcher develops ‘fat burning’ molecule that has implications for treatment of obesity

Researchers have recently identified a small mitochondrial uncoupler, named BAM15, that decreases the body fat mass of mice without affecting food intake and muscle mass or increasing body temperature. Additionally, the molecule decreases insulin resistance and has beneficial effects on oxidative stress and inflammation. The findings hold promise for future treatment and prevention of obesity, diabetes, and especially nonalcoholic steatohepatitis (NASH), a type of fatty liver disease that is characterized by inflammation and fat accumulation in the liver.

The mitochondria are commonly referred to as the powerhouses of the cell. The organelle generates ATP, a molecule that serves as the energy currency of the cell, which powers body movement and other biological processes that help our body to function properly. In order to make ATP, nutrients need to be burned and a proton motive force (PMF) needs to be established within the mitochondria. The PMF is generated from a proton gradient, where there is a higher concentration of protons outside of the inner membrane and a lower concentration of protons in the matrix, or the space within the inner membrane. The cell creates ATP whenever protons pass through an enzyme called ATP synthase, which is embedded in the membrane. Hence, nutrient oxidation, or nutrient burning, is coupled to ATP synthesis. Mitochondrial uncouplers transport protons into the matrix by bypassing ATP synthase, which throws off the PMF. To reestablish the gradient, protons must be exported out of the mitochondrial matrix. As a result, the cell begins to burn fuel at higher than necessary levels.

Knowing that these molecules can change a cell’s metabolism, researchers wanted to be sure that the drug was reaching its desired targets and that it was, above all, safe. Through a series of mouse studies, the researchers found that BAM15 is neither toxic, even at high doses, nor does it affect the satiety center in the brain, which tells our body if we are hungry or full. Another side effect of previous mitochondrial uncouplers was increased body temperature. Researchers measured the body temperature of mice who were fed BAM15. They found no change in body temperature. In the BAM15 mouse studies, animals ate the same amount as the control group – and they still lost fat mass.

Mitochondrial uncoupler BAM15 reverses diet-induced obesity and insulin resistance in mice

Obesity is a health problem affecting more than 40% of US adults and 13% of the global population. Anti-obesity treatments including diet, exercise, surgery and pharmacotherapies have so far failed to reverse obesity incidence. Herein, we target obesity with a pharmacotherapeutic approach that decreases caloric efficiency by mitochondrial uncoupling. We show that a recently identified mitochondrial uncoupler BAM15 is orally bioavailable, increases nutrient oxidation, and decreases body fat mass without altering food intake, lean body mass, body temperature, or biochemical and haematological markers of toxicity.

BAM15 decreases hepatic fat, decreases inflammatory lipids, and has strong antioxidant effects. Hyperinsulinemic-euglycemic clamp studies show that BAM15 improves insulin sensitivity in multiple tissue types. Collectively, these data demonstrate that pharmacologic mitochondrial uncoupling with BAM15 has powerful anti-obesity and insulin sensitizing effects without compromising lean mass or affecting food intake.

Molecular Changes in the Lens of the Eye as a Potential Biomarker of Biological Age

The search for viable biomarkers of aging is an active field of research. The ability to rapidly and cheaply assess biological age, the burden of cell and tissue damage and dysfunction that causes disease and mortality, would greatly speed the development of rejuvenation therapies. At present it is costly and slow to demonstrate that any given approach to rejuvenation actually works: one needs to run a life span study, which is prohibitively expensive in mice and simply impractical in humans. What is needed is a test that can be carried out immediately before and immediately after an intervention, and which accurately assesses the state of aging.

Numerous approaches to a biomarker of aging have been suggested, or are at various stages of development. Aging clocks based on selected epigenetic markers, protein levels, or portions of the transcriptome are all popular approaches. Weighted algorithmic combinations of simple metrics such as grip strength and walking speed have also been explored. Other approaches exist. For example, in today’s research materials, scientists suggest that assessment of molecular changes in the lens of the eye is worthy of consideration.

The challenge with all of these biomarkers of biological age is that it is very unclear as to how they connect specifically to the underlying causes of aging. It isn’t unreasonable to think that some biomarkers reflect only certain forms of the cell and tissue damage of aging, or certain downstream consequences rather than all of them. Which is fine if only looking and not intervening. But this means that one can’t just run an assessment of a specific approach to rejuvenation coupled with a specific biomarker, and have any great confidence that the numbers will be meaningful at the end of the study. At the present time, any biomarker used must be calibrated against a specific rejuvenation therapy in order to determine how it responds. This rather defeats the point of the exercise, as that calibration is going to require numerous life span studies.

Eye scanner detects molecular aging in humans

All people age, but individuals do so at different rates, some faster and others slower. While this observation is common knowledge, there is no universally accepted measure of biological aging. Numerous aging-related metrics have been proposed and tested, but no marker to date has been identified or noninvasive method developed that can accurately measure and track biological aging in individuals. In what is believed to be the first study of its kind, researchers have discovered that a specialized eye scanner that accurately measures spectroscopic signals from proteins in lens of the eye can detect and track biological aging in living humans.

“The lens contains proteins that accumulate aging-related changes throughout life. These lens proteins provide a permanent record of each person’s life history of aging. Our eye scanner can decode this record of how a person is aging at the molecular level. Eye scanning technology that probes lens protein affords a rapid, noninvasive, objective technique for direct measurement of molecular aging that can be easily, quickly, and safely implemented at the point of care. Such a metric affords potential for precision medical care across the lifespan.”

In Vivo Quasi-Elastic Light Scattering Eye Scanner Detects Molecular Aging in Humans

The absence of clinical tools to evaluate individual variation in the pace of aging represents a major impediment to understanding aging and maximizing health throughout life. The human lens is an ideal tissue for quantitative assessment of molecular aging in vivo. Long-lived proteins in lens fiber cells are expressed during fetal life, do not undergo turnover, accumulate molecular alterations throughout life, and are optically accessible in vivo.

We used quasi-elastic light scattering (QLS) to measure age-dependent signals in lenses of healthy human subjects. Age-dependent QLS signal changes detected in vivo recapitulated time-dependent changes in hydrodynamic radius, protein polydispersity, and supramolecular order of human lens proteins during long-term incubation (~1 year) and in response to sustained oxidation (~2.5 months) in vitro. Our findings demonstrate that QLS analysis of human lens proteins provides a practical technique for noninvasive assessment of molecular aging in vivo.

An Example to Illustrate Why Navitoclax is Not a Suitable Clinical Senolytic Drug

Senolytic therapies are those that selectively destroy senescent cells. Cells that become senescent grow in size, cease to replicate, and generate a potent mix of molecules known as the senescence-associated secretory phenotype (SASP). Senescence occurs at the Hayflick limit on cellular replication, or in response to cell damage and a toxic local environment. The SASP provokes the immune system into an inflammatory state, disrupts tissue structure and function, and encourages nearby cells to also become senescent. It is useful in the short term, in the context of wound healing and cancer suppression for example, but when present for the long-term, the SASP is an important cause of degenerative aging. A significant fraction of aging and age-related disease is driven by the accumulation of senescent cells throughout the body, and hence the research community is quite interested in finding ways to get rid of these errant cells.

The earliest discovered senolytic small molecule drugs are chemotherapeutics. It is fair to say that they are selective for senescent cells, but in some cases far from selective enough. They kill a lot of non-senescent cells and, further, cause all sorts of problematic and potentially serious side-effects. In addition, drugs such as the small molecules targeting Bcl-2 family proteins, particularly navitoclax, tend to require a few weeks of dosing at chemotherapeutic levels to generate senolytic effects. This is as opposed to the few doses or intermittent doses of the arguably more effective senolytic chemotherapeutic dasatinib. Less of a chemotherapeutic drug is almost always a good thing.

The open access paper I’ll point out today provides an additional incentive to avoid navitoclax as a senolytic treatment. It does indeed kill senescent cells in aged tissues, but it is just too toxic, with too many harmful side-effects, for use in the clinic. This is the case, at least, without the use of one or more of the clever adaptations to limit its harms that have been proposed of late. Whether or not these approaches make it into clinical use is somewhat hit and miss, however, given that there are many other alternative senolytic therapies presently under development.

The Senolytic Drug Navitoclax (ABT-263) Causes Trabecular Bone Loss and Impaired Osteoprogenitor Function in Aged Mice

Senescence is a cellular defense mechanism that helps cells prevent acquired damage, but chronic senescence, as in aging, can contribute to the development of age-related tissue dysfunction and disease. Previous studies clearly show that removal of senescent cells can help prevent tissue dysfunction and extend healthspan during aging. Senescence increases with age in the skeletal system, and selective depletion of senescent cells or inhibition of their senescence-associated secretory phenotype (SASP) has been reported to maintain or improve bone mass in aged mice.

This suggests that promoting the selective removal of senescent cells, via the use of senolytic agents, can be beneficial in the treatment of aging-related bone loss and osteoporosis. Navitoclax (also known as ABT-263) is a chemotherapeutic drug reported to effectively clear senescent hematopoietic stem cells, muscle stem cells, and mesenchymal stromal cells in previous studies, but its in vivo effects on bone mass had not yet been reported. Therefore, the purpose of this study was to assess the effects of short-term navitoclax treatment on bone mass and osteoprogenitor function in old mice.

Aged (24 month old) male and female mice were treated with navitoclax (50 mg/kg body mass daily) for 2 weeks. Surprisingly, despite decreasing senescent cell burden, navitoclax treatment decreased trabecular bone volume fraction in aged female and male mice (-60.1% females, -45.6% males), and bone marrow stromal cells (BMSC) derived osteoblasts from the navitoclax treated mice were impaired in their ability to produce a mineralized matrix (-88% females, -83% males). Moreover, in vitro administration of navitoclax decreased BMSC colony formation and calcified matrix production by aged BMSC-derived osteoblasts, similar to effects seen with the primary BMSC from the animals treated in vivo. Navitoclax also significantly increased metrics of cytotoxicity in both male and female osteogenic cultures.

Taken together, these results suggest a potentially harmful effect of navitoclax on skeletal-lineage cells that should be explored further to definitively assess navitoclax’s potential (or risk) as a therapeutic agent for combating age-related musculoskeletal dysfunction and bone loss.

Fitting Senescent Cells into a Modified Amyloid Cascade Hypothesis of Alzheimer’s Disease

The amyloid cascade hypothesis is the earliest coherent view of the development of Alzheimer’s disease. In this view, the condition begins with the slow aggregation of amyloid-β over many years, and this process sets up the cell dysfunction and chronic inflammation that allows much more harmful later stage of tau aggregation to get underway in earnest. This hypothesis has dominated research and development for many years, and across this period of time, alternative views and approaches to the condition gained little traction and funding.

Therapies based on clearance on amyloid-β took a long time to achieve the goal of reducing amyloid-β levels in humans. This was only demonstrated in the past few years, and, unfortunately, failed to produce meaningful patient benefits. This has led to considerable unrest and rebellion against the consensus in the Alzheimer’s research community. There is a great deal of renewed theorizing, and new directions in the development of therapies are finally seeing greater funding and attention.

One important new direction is the clearance of senescent supporting cells from the brain. Animal data strongly suggests that senescent microglia and astrocytes are causing considerable harm in the aging brain, and are particularly important in Alzheimer’s disease. One of the early senolytic drugs, dasatinib, can pass the blood-brain barrier to selectively destroy senescent cells in the brain. It has been used to reverse neurodegeneration and neuroinflammation in animal models of Alzheimer’s disease. Is it the case that amyloid-β accumulation creates a greater burden of cellular senescence in old age, and once a significant senescent cell population is established, it doesn’t much help to remove the amyloid-β? Maybe so.

Senescence as an Amyloid Cascade: The Amyloid Senescence Hypothesis

Due to their postmitotic status, the potential for neurons to undergo senescence has historically received little attention. This lack of attention has extended to some non-postmitotic cells as well. Recently, the study of senescence within the central nervous system (CNS) has begun to emerge as a new etiological framework for neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD).

The presence of senescent cells is known to be deleterious to non-senescent neighboring cells via development of a senescence-associated secretory phenotype (SASP) which includes the release of inflammatory, oxidative, mitogenic, and matrix-degrading factors. Senescence and the SASP have recently been hailed as an alternative to the amyloid cascade hypothesis and the selective killing of senescence cells by senolytic drugs as a substitute for amyloid beta (Aß) targeting antibodies.

Here we call for caution in rejecting the amyloid cascade hypothesis and to the dismissal of Aß antibody intervention at least in early disease stages, as Aß oligomers (AßO), and cellular senescence may be inextricably linked. We will review literature that portrays AßO as a stressor capable of inducing senescence. We will discuss research on the potential role of secondary senescence, a process by which senescent cells induce senescence in neighboring cells, in disease progression. Once this seed of senescent cells is present, the elimination of senescence-inducing stressors like Aß would likely be ineffective in abrogating the spread of senescence. This has potential implications for when and why AßO clearance may or may not be effective as a therapeutic for AD.

The selective killing of senescent cells by the immune system via immune surveillance naturally curtails the SASP and secondary senescence outside the CNS. Immune privilege restricts the access of peripheral immune cells to the brain parenchyma, making the brain a safe harbor for the spread of senescence and the SASP. However, an increasingly leaky blood brain barrier (BBB) compromises immune privilege in aging AD patients, potentially enabling immune infiltration that could have detrimental consequences in later AD stages. Rather than an alternative etiology, senescence itself may constitute an essential component of the cascade in the amyloid cascade hypothesis.

Senescent Cardiomyocytes in Cardiovascular Disease

Senescent cells accumulate in tissues throughout the body with age. Cells constantly become senescent as a result of wound healing, cancer suppression, the Hayflick limit on cellular replication, or damage and a toxic local environment. Near all are destroyed quite quickly, either via programmed cell death or by the immune system. It remains to be rigorously determined as to whether the growth in numbers of senescent cells with age is an imbalance of slowed clearance and increased production, or whether a tiny fraction of all senescent cells manage to evade destruction and linger for the long term.

What is certain is that the burden of senescent cells is very damaging to health. Senescent cells generate the senescence-associated secretory phenotype, a secreted mix of molecules that causes chronic inflammation, destructive remodeling of surrounding tissue, and dysfunction of nearby cells. A comparatively small number of senescent cells can cause meaningful loss of organ function and the onset of age-related disease. This is thus one of the important contributing causes of aging.

The research community is exploring the consequences of cellular senescence tissue by tissue, starting with those most important to age-related mortality. In the heart, cellular senescence produces fibrosis, a disarray of normal tissue maintenance processes that manifests as inappropriate deposition of scar-like collagen structures. It is also connected to the ventricular hypertrophy that leads to heart failure. Targeted removal of senescent cells has been shown to reverse these pathologies in mice, and as a consequence there is considerable interest in further exploration of the biochemistry of senescence in the aging heart.

Cardiomyocyte Senescence and Cellular Communications Within Myocardial Microenvironments

The heart is an organ with high energy demand: mitochondria content in cardiomyocytes is up to 70%. During aging and stress conditions, the metabolic pattern changes in cardiomyocytes, which is critically involved in the regulation of cardiomyocyte dysfunction and senescence. The non-myocytes (endothelial cells, fibroblasts, and immune cells) in the local microenvironment also contribute to the (dys)function/senescence of cardiomyocytes. In turn, the senescent cardiomyocytes modulate the microenvironment to contribute to functional compensatory response or decompensatory remodeling and cardiac dysfunction.

Although cell senescence plays essential roles in wound healing, limiting atherosclerotic plaque size, and preventing infections, the effects of cell senescence can be detrimental or beneficial. The exact roles of senescent cells that contribute to aging and age-related diseases can be named “senescaging”. Further studies are still needed to explore the physiological and pathological functions of senescent cardiomyocyte during cardiac development, regeneration, and pathological remodeling, and to elucidate how senescaging contributes to cardiac aging and disease. Specifically, more studies are needed to answer whether cardiomyocyte senescence critically contributes to cardiac aging and the related heart failure with preserved ejection fraction (HFpEF).

Microenvironmental non-myocytes function as central regulators of cardiomyocyte senescence, and metabolism switch is important for the homeostasis and senescence of cardiomyocytes. As thus, an interesting point is whether these non-myocytes affect the metabolic pattern of cardiomyocyte undergoing senescence. Also, studies are needed to explore how metabolism alternations in non-myocytes contribute to cardiomyocyte senescence and cardiac aging. Many studies have been carried out to study the effects of non-myocytes on cardiomyocyte senescence. Some studies also explored the paracrine effects of cardiomyocytes on non-myocytes. However, our knowledge about the effects of senescent cardiomyocytes on microenvironmental non-myocytes is few and further efforts are needed.

An interesting question is whether cardiomyocyte senescence and the myocardial microenvironment could serve as targets for anti-aging drugs such as the popular senolytics. Senolytics were recently reported to repress senescence and inhibit cardiac disease such as myocardial infarction and repress age-related vasomotor dysfunction and atherosclerosis. Further studies are still needed to elucidate how senolytics target cardiomyocyte senescence and local microenvironment, and that whether other anti-aging drugs could repress the senescaging of myocardial microenvironment.

Blood Drainage from the Brain Slows with Age, Leading to Ventriculomegaly

As noted here, the circulation of blood through the brain slows in specific ways with increasing age. Taken as a biomarker, this correlates with one of the noteworthy structural changes that take place in the aging brain, the enlargement of the ventricles that results from slowed fluid drainage. This is perhaps worth comparing with the work of recent years on the impaired drainage of cerebrospinal fluid in the aging of the brain, though this is more a matter of failing to remove molecular waste rather than fluid dynamics issues leading to damage to tissue structure. Another line of research to consider is the loss of capillary density in tissues with age, as perhaps this is an important mechanism involved in an age-related slowing of the passage of blood through brain tissue.

Ventriculomegaly is an abnormal condition in which fluid accumulates in the ventricles of the brain without properly draining, making them enlarged. Although ventricular enlargement within normal range is not itself considered a disease, when left unchecked it can lead to ventriculomegaly and dementia resulting from normal pressure hydrocephalus. In their study, the team found that ventriculomegaly was associated with changes in blood circulation of the brain.

After blood circulates through the brain providing necessary oxygen, the deoxygenated blood must return to the heart though our veins. This happens through two pathways, one draining blood from regions close to the surface of the brain, and the other from areas deep in the brain. By using MRI to measure changes in blood flow, the team recently found that as we age, the time it takes for blood to drain through these two pathways becomes out of sync. The result is a time lag between the deep drainage pathway and the surface pathway, which increases with age.

In the new study, the researchers found that in healthy aging, the time lag in circulation grows at almost the same rate as enlarging ventricles, but begins slightly earlier. A diagnostic MRI that measures an individual’s lag between the two drainage pathways might be a good biomarker for the aging brain, and a possible predictor of ventriculomegaly. Because dementia resulting from hydrocephalus can be reversed by removing the fluid that builds up in the ventricles, early diagnosis is critical.

Loss of Visual Acuity Correlates with Dementia Risk

Many aspects of aging correlate with one another, even those with quite different underlying mechanisms and proximate causes. The various forms of root cause damage that result in the aging process, as well as their downstream consequences, all interact with one another. So whether or not any specific correlation teaches us anything about the way in which aging works under the hood is very dependent on the details. That loss of vision and hearing correlate with dementia risk is known, but the relative contribution of different mechanisms is up for debate. How much is due to similar biochemical mechanisms of damage in nervous system tissues, and how much is due to loss of sensory stimulation, for example.

Recent studies reported that the incidence of dementia in western countries may be declining whereas low and middle income countries are predicted to have the largest increase in incident dementia. This discrepancy is suggested to be due to the differences in the effective management of cardiovascular disease, hypertension, and diabetes in these regions. However, even though early recognition of risk factors for dementia is of utmost priority, the sporadic incidence of dementia is a challenge in preventive medicine.

Previous studies have suggested that an association exists between vision loss and cognitive impairment. Low vision and blindness are commonly seen in the older population as the risk of developing cataract; age-related macular degeneration and glaucoma increase with advancing age. Despite the body of evidence, there are few reports regarding causal relationships or direct association between low vision and dementia. A clear understanding of this association may facilitate the development of strategies for reducing the burden of cognitive impairment.

The National Health Insurance Service (NHIS) database has recently become accessible to researchers in Korea. This large-scale database permits the identification of the longitudinal incidence of diseases and allows for the analysis of the association between diseases and health conditions. Using the six levels of disability of the Korean rating system, an individual with low vision can be classified depending on his/her visual acuity. Employing the disability grade used in Korea, we were able to investigate the impact of low vision on incident dementia by using a nationwide population-based cohort that includes over 1.5 million Koreans.

Statistical analysis showed that subjects with more severe visual impairments have a higher risk of dementia, Alzheimer’s disease, and vascular dementia after adjusting for compounding variables. The hazard ratios (HRs) of dementia increased significantly as visual acuity worsened: 1.444 for visual acuity (VA) < 1.0, 1.734 for VA < 0.3, 1.727 for VA < 0.1, and 1.991 for visual loss. Baseline visual loss and visual impairment were positively associated with the risk of dementia, Alzheimer’s disease, and vascular dementia. From the results of this nationwide population-based cohort study, we suggest that there is a significant increase in the incidence of dementia in subjects with low vision.

Quantifying Loss of Kidney Function with Age in a Human Population

Kidney function is critical to health, but, as is the case for all organs, the kidneys declines with age. The damage of aging produces harmful outcomes in many ways. For example, hypertension causes structural pressure damage in sensitive tissues in the kidneys. Further, senescent cells and other sources of chronic inflammation disrupt normal tissue maintenance processes in the kidneys, leading to the scar-like collagen deposits of fibrosis. In turn, loss of kidney function accelerates many other aspects of aging, including neurodegeneration and the onset of cognitive decline.

An international study that has been carried out on nearly 3000 people in Norway, Germany, and Iceland, shows that our kidney function deteriorates with age, even if we do not have any other diseases. One of the groups that have participated in the study consists of over 1600 people and stems from the Tromsø Study, which is Norway’s most comprehensive and best participated population study throughout 40 years. This group has been through the different examinations three times; between 2007 to 2009, 2013 to 2015, and 2018 to 2020.

“What we see is that what happens in our kidneys when we age is representative of all the other things that happen in our bodies. The kidney function deteriorates, not because we get ill, but as part of ageing. Loss of kidney function is something that happens to all humans and is thus a way to determine ageing in general. There is still variation as to how quickly this happens, and we still do not have good answers as to why this variation occurs. We have examined many factors that can play a part as to why some of us experience larger loss of kidney function than others.”

The researchers use a precise method of measuring kidney function. They inject a substance into the blood veins that only separates into the kidneys, and let a few hours pass before they measure how much of the substance remains in the blood. This gives a measure of the kidney’s ability to remove toxins and waste products. Researchers explain that more people may experience loss of kidney function as it becomes more common to survive diseases like cancer and heart and vascular diseases.

Threonine Restriction Promotes Health in Mice

Calorie restriction, eating up to 40% fewer calories while maintaining optimal micronutrient intake, improves health and reliably extends life in most species. In humans it produces robust improvements in health, but we experience a much lesser degree of life extension than short-lived species such as mice. Calorie restriction research has given rise to a number of lines of work in which specific dietary components (such as individual essential amino acids) are restricted, to try to identify which of these components are responsible for the benefits. A sizable fraction of the calorie restriction response is thought to be triggered by low dietary intake of the essential amino acid methionine, for example. In contrast to that body of work, researchers here restrict threonine, another essential amino acid, in laboratory mice, and observe an interesting set of benefits.

The current classification of essential amino acids (EAA) is based on the nutritional requirements for growth and vitality under nil dietary supply of an amino acid. However, humans rarely face dramatic protein/amino acid insufficiency, and for the first time in human history, nutritional excesses mean the amount of overweight people outnumber the amount of underweight people on a global scale. This calls for a reconsideration of amino acid functions in nutrition, now based upon health-related criteria.

One approach is dietary protein dilution (DPD), where protein is reduced and replaced by other nutrient sources, and is distinct from caloric restriction. Unlike severe protein/amino acid restriction, which is not compatible with vitality, moderate DPD promotes longevity in multiple species including flies, rodents, and perhaps humans. Furthermore, DPD also affects health-span and preclinical studies have demonstrated that DPD can retard age-related diseases such as cancer, type 2 diabetes, and dyslipidemia/fatty liver disease. Notably, dietary protein intake rates are positively related to type 2 diabetes risk as well as all-cause mortality in humans.

Here, by mimicking amino acid supply from a casein-based diet, we demonstrate that restriction of dietary EAA, but not non-EAA, drives the systemic metabolic response to total amino acid deprivation; independent from dietary carbohydrate supply. Furthermore, systemic deprivation of threonine and tryptophan, independent of total amino acid supply, are both adequate and necessary to confer the systemic metabolic response to amino acid restriction.

Dietary threonine restriction (DTR) retards the development of obesity-associated metabolic dysfunction. Liver-derived fibroblast growth factor 21 is required for the metabolic remodelling with DTR. Strikingly, hepatocyte-selective establishment of threonine biosynthetic capacity reverses the systemic metabolic response to DTR. Taken together, our studies of mice demonstrate that the restriction of EAA are sufficient and necessary to confer the systemic metabolic effects of DPD.

Retraining the Immune System to Turn Off Autoimmunity

This interesting study suggests that it may be possible to turn off many forms of autoimmunity by inducing tolerance, in a comparatively simple manner, to the specific fragment of a protein that is causing an immune reaction. There are autoimmunities in which the specific trigger is poorly understood, including the only vaguely cataloged and no doubt highly variable autoimmunities of aging, but many other conditions for which this might be a useful approach.

Autoimmune diseases are caused when the immune system loses its normal focus on fighting infections or disease within and instead begins to attack otherwise healthy cells within the body. In the case of multiple sclerosis (MS), the body attacks proteins in myelin – the fatty insulation-like tissue wrapped around nerves – which causes the nerves to lose control over muscles.

Scientists examined the intricate mechanisms of the T-cells that control the body’s immune system and found that the cells could be ‘re-trained’ to stop them attacking the body’s own cells. In the case of multiple sclerosis, this would prevent the body from attacking the Myelin Basic Protein (MBP) by reprogramming the immune system to recognise the protein as part of itself.

The first stage showed that the immune system can be tricked into recognising MBP by presenting it with repeated doses of a highly soluble fragment of the protein that the white blood cells respond to. By repeatedly injecting the same fragment of MBP, the process whereby the immune system learns to distinguish between the body’s own proteins and those that are foreign can be mimicked. The process, which is a similar type of immunotherapy to that previously used to desensitise people against allergies, showed that the white blood cells that recognise MBP switched from attacking the proteins to actually protecting the body.

The second stage, saw gene regulation specialists probe deep within the white blood cells that react to MBP to show how genes are rewired in response to this form of immunotherapy to fundamentally reprogram the immune system. The repeated exposure to the same protein fragment triggered a response that turns on genes that silence the immune system instead of activating it. These cells then had a memory of this exposure to MBP embedded in the genes to stop them setting off an immune response. When T cells are made tolerant, other genes which function to activate the immune system remain silent.

Blood Pressure Control Increases Life Expectancy Even in the Most Frail Elderly People

Chronically raised blood pressure, or hypertension, is highly damaging to tissues throughout the body. It is an important mechanism linking the molecular damage of aging to gross structural damage to organs, causing loss of function, age-related disease, and death. Many of the underlying causes of aging lead to stiffness of blood vessel walls, from cross-linking in the extracellular matrix to the effects of senescent cell signaling on vascular smooth muscle cells. That stiffness causes dysfunction in the regulation of blood pressure, which in turn causes pressure damage, increased pace of the development of atherosclerosis, and other age-related issues.

Taking blood pressure medication as prescribed helped even the frailest elderly people (65 and older) live longer, and the healthiest older people had the biggest survival boost, according to a large study in northern Italy. Researchers reviewed data on almost 1.3 million people aged 65 and older (average age 76) in the Lombardy region of northern Italy who had three or more high blood pressure medication prescriptions in 2011-2012. Examining the public health care database, researchers calculated the percentage of time over the next seven years (or until death) that each person continued to receive the medications. Because almost all medications are free or low-cost and dispensed by the public health service, this corresponds roughly to people’s adherence in using the medication in Italy.

Researchers compared roughly 255,000 people who died during the 7-year follow-up with age-, gender-, and health-status-matched controls who survived and divided them into four groups of health status: good, medium, poor, or very poor. The probability of death over 7-years was 16% for people rated in good health at the beginning of the study. Mortality probability increased progressively to 64% for those rated in very poor health.

Compared with people with very low adherence to blood pressure medications, meaning dispensed pills covered less than 25% of the time period, people with high adherence to blood pressure medications, meaning more than 75% of the time period covered, were: (a) 44% less likely to die if they started in good health; and (b) 33% less likely to die if they started in very poor health. A similar pattern was seen with cardiovascular deaths. The greatest survival benefit was among the people who started in good health, and the most modest survival benefit was in those who started in very poor health. “Our findings definitely suggest that even in very frail people, antihypertensive treatment reduces the risk of death; however, the benefits may be smaller in this group.”

Repetitive Elements as a Transcriptomic Biomarker of Aging

Retrotransposons are receiving more attention in the context of aging these days. They are the remnants of ancient viruses, capable of copying themselves around the genome. The mechanisms repressing this copying tend to fail with age, and retrotransposons become a potential source of DNA damage and metabolic disarray. They are not the only class of repetitive elements in the genome, however. Here, researchers discuss the broader category of repetitive elements and their increasing presence with advancing age. Assessing repetitive element activity, such as by looking for them in the transcriptome, may be a potential biomarker of biological age.

One particularly large and often-ignored fraction of the human genome (more than 60%) is composed of repetitive elements (RE). These include: types 1 and 2 transposons (retrotransposons and DNA transposons, respectively), some of which can self-copy and reinsert into new locations; terminal repeats at the ends of retrotransposons; and tandem repeats, including sequences common to centromeres, chromatin, and other structured genome regions. Most RE are chromatinized and suppressed, but certain retrotransposons remain active in humans and may be involved in aging. Indeed, studies in mice and other model organisms have shown that active/transposable RE, in particular, contribute to the aging process, although most evidence points to RE activation later in life (e.g., in senescence).

The potential for RE in general to serve as a transcriptomic marker of aging has not been investigated, especially in humans, but we and others have reported a generic accumulation of RE transcripts (i.e., not only active RE) in age-related neurodegenerative processes and diseases. Evidence also indicates that chromatin maintenance declines with aging, which could increase general transcriptional accessibility of RE. As such, age-related changes in global RE transcript levels could be a good transcriptomic/mechanistic marker of aging.

Here, we used multiple RNA-seq datasets generated from human samples and Caenorhabditis elegans and found that most RE transcripts (a) accumulate progressively with aging; (b) can be used to accurately predict age; and (c) may be a good marker of biological age. The strong RE/aging correlations we observed are consistent with growing evidence that RE transcripts contribute directly to aging and disease.

Stiffening of the Extracellular Matrix Contributes to Age-Related Muscle Impairment

In this interesting open access paper, the authors explore the contribution of changes in the extracellular matrix to the deterioration of muscle function that takes place with aging. The extracellular matrix is produced and maintained by cells, and gives tissue its structural properties. It is a complex arrangement of molecules such as collagen and elastin, continually updated by cells, and not always for the better as aging progresses. Chronic inflammation, for example, provokes excessive and inappropriate deposition of collagen. Further, elastin molecules tend not be replaced at the same pace as they are damaged or broken down. In addition, persistent cross-links form between extracellular matrix molecules, altering structural properties such as elasticity. This is most apparent in skin and blood vessels, but, as the researchers here point out, these are not the only places in the body in which changes in the extracellular matrix are important.

In humans, the stiffness of the muscle-tendon complex in situ increases with aging, and this is mainly attributed to an increase in muscle stiffness, while tendons display greater compliance. Importantly, the age-related increase in stiffness of the muscle-tendon complex has been considered relevant to the preservation of eccentric force in the elderly. Whole muscle stiffness depends on the mechanical properties of muscle fibers and of extracellular matrix (ECM), and it is still debated whether muscle fibers or ECM are the determinants of such change.

To answer this question, we compared the passive stress generated by elongation of fibers alone and arranged in small bundles in young healthy (Y: 21 years) and elderly (E: 67 years) subjects. The physiological range of sarcomere length 2.5-3.3 μm was explored. The area of ECM between muscle fibers was determined on transversal sections with picrosirius red, a staining specific for collagen fibers.

The passive tension of fiber bundles was significantly higher in E compared to Y at all sarcomere lengths. However, the resistance to elongation of fibers alone was not different between the two groups, while the ECM contribution was significantly increased in E compared to Y. The proportion of muscle area occupied by ECM increased from 3.3% in Y to 8.2% in E. When the contribution of ECM to bundle tension was normalized to the fraction of area occupied by ECM, the difference disappeared. We conclude that, in human skeletal muscles, the age-related reduced compliance is due to an increased stiffness of ECM, mainly caused by collagen accumulation.

Regular Physical Activity Reverses Frailty in the Old

There is considerable evidence for the proposition that older people engage in too little physical activity. Our modern societies of comfort and our engines of transport enable a sedentary lifestyle, to our detriment. The harms done by remaining sedentary are large enough that physical activity begins to look like an effective intervention. It reduces mortality, slows onset of age-related disease, and, as noted here, can reverse the progression of age-related frailty.

Maintaining a healthy lifestyle in older age is associated with a lower level of frailty. However, studies on the association between physical activity (PA) and frailty among older adults show contradictory results. Some studies suggest that regular PA may delay the onset of frailty and reduce its severity, but others found that PA was not associated with a decreased risk for frailty among older adults. Second, most of the longitudinal studies on PA and frailty examine baseline PA only in relation to changes in frailty, and evidence on the association between change in PA and frailty is limited. Additionally, most studies on PA and frailty have been conducted in adults aged 50 to 70 years, and evidence on the longitudinal association between PA and frailty in adults older than 70 years is relatively scarce.

Most previous studies on PA and frailty have focused on physical frailty only, and to date there has been little research into psychological and social frailty. Therefore, the aim of our study was to examine the longitudinal association between frequency of moderate PA and overall, physical, psychological, and social frailty among community-dwelling older adults older than 70 years. Second, we assessed the association between a 12-month change in frequency of moderate PA and frailty.

Participants who undertook moderate PA with a regular frequency at baseline were less frail at 12-month follow-up than participants with a low frequency. Participants who undertook moderate PA with a continued regular frequency were least frail at baseline and at 12-month follow-up. After controlling for baseline frailty and covariates, compared with participants with a continued regular frequency, participants with a decreased frequency were significantly more overall, physically, psychologically, and socially frail at 12-month follow-up. Participants with a continued low frequency were significantly more overall, physically, psychologically, and socially frail at 12-month follow-up. The 12-month follow-up frailty level of participants who undertook moderate PA with an increased frequency was similar to those with a continued regular frequency.

CD9 Expression in Cellular Senescence and Atherosclerosis

Cellular senescence is important in the progression of aging, and targeted elimination of senescent cells has been shown to reverse the course of many age-related conditions in animal studies. Atherosclerosis is the build up of fatty plaques in blood vessels, narrowing and weakening to the point of eventual rupture. This occurs because macrophage cells become dysfunctional and fail in their task of maintaining these tissues. Some macrophages in atherosclerotic plaques are senescent, and these cells, as well as senescent cells in the endothelial and other tissues of blood vessels, produce an inflammatory environment that encourages futher macrophage dysfunction.

Removal of these senescent cells has been shown to slow the progression of atherosclerosis in animal models. Here, researchers investigate one mechanism by which cellular senescence arises in blood vessel endothelial tissues. They show that interfering in this mechanism can reduce the burden of cellular senescence in blood vessel walls, and thus slow the progression of atherosclerosis.

CD9, a tetraspanin membrane protein, is known to regulate cell adhesion and migration, cancer progression and metastasis, immune and allergic responses, and viral infection. CD9 is upregulated in senescent endothelial cells, neointima hyperplasia, and atherosclerotic plaques. However, its role in cellular senescence and atherosclerosis remains undefined.

We investigated the potential mechanism for CD9-mediated cellular senescence and its role in atherosclerotic plaque formation. CD9 knockdown in senescent human umbilical vein endothelial cells significantly rescued senescence phenotypes, while CD9 upregulation in young cells accelerated senescence. CD9 regulated cellular senescence through a phosphatidylinositide 3 kinase-AKT-mTOR-p53 signal pathway. CD9 expression increased in arterial tissues from humans and rats with age, and in atherosclerotic plaques in humans and mice.

Anti-mouse CD9 antibody noticeably prevented the formation of atherosclerotic lesions in ApoE knockout mice and Ldlr knockout mice. Furthermore, CD9 ablation in ApoE knockout mice decreased atherosclerotic lesions in aorta and aortic sinus. These results suggest that CD9 plays critical roles in endothelial cell senescence and consequently the pathogenesis of atherosclerosis, implying that CD9 is a novel target for prevention and treatment of vascular aging and atherosclerosis.