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  • Kimer Med Founded to Develop the DRACO Antiviral Strategy
  • We Should Actually Try to Treat Aging for a Change
  • Connecting the Immune Response to Amyloid-β Aggregation in Alzheimer’s Disease via IFITM3
  • Targeting Cellular Senescence to Heal Non-Healing Wounds
  • Hormone Therapy in Postmenopausal Women Correlates with Lesser Senescent Cell Signaling
  • Approaches to Optimize Growth of Muscles in Response to Resistance Training in Old People
  • HDAC9 Inhibition Slows the Progression of Osteoporosis in Old Mice
  • Raised Blood Pressure is So Harmful that Reductions are Beneficial Even Without Addressing Underlying Causes
  • Mechanisms by which Hearing Loss Might Contribute to the Onset of Dementia
  • An Interview with a Principal Investigator at Calico
  • Long Lived Humans Do Not Exhibit Fewer Harmful Gene Variants
  • A Meta-Analysis of the Ability of Exercise to Reduce Age-Related Mortality
  • A Damage-Based View of Aging, Offering the Hope of Rejuvenation through Repair
  • Greater Fitness Correlates with Lower White Matter Hyperintensity Volume in the Aging Brain
  • Dysfunction of the Blood-Brain Barrier as an Early Stage in the Progression to Dementia

Kimer Med Founded to Develop the DRACO Antiviral Strategy

Today’s good news is that a biotech startup, Kimer Med, has been founded to develop the DRACO approach to defeating viral infections. Those of us who have been following developments in antiviral technologies that might be applied to persistent infections relevant to aging, such as cytomegalovirus (CMV) and other herpesviruses, may recall a burst of interest in DRACO some years ago, particularly the research crowdfunding efforts in 2015 and 2016.

DRACO (Double-stranded RNA Activated Caspase Oligomerizer) works by selectively killing cells that exhibit one of the distinctive signs of viral replication. This replication produces long double-stranded RNA, whereas mammalian cells only produce short double-stranded RNA in the normal course of events. It is possible to deliver a form of molecule into the cell that interacts with only long double-stranded RNA and triggers cell death via caspase induced apoptosis as a result, depriving the viral particles of their factory. The fine details of the approach are outlined in the original 2011 paper, and DRACO has been proven to do quite well by a few different research groups in several different animal models of viral infection.

There are two reasons as why this is interesting. Firstly, it can be applied, with little additional work on a per-case basis, to a broad range of virus types, becoming a potentially near-universal antiviral platform. The economics of such a technology look very good in comparison to most other antiviral approaches. Secondly, it has the potential to clear the body of persistent viruses such as CMV. CMV causes great harm to the immune system over a lifetime because it can only be suppressed by present strategies, never fully cleared from the body. The evidence strongly suggests that it is one of the major causes of age-related immunosenescence.

Unfortunately, DRACO went the way of all too many novel research initiatives. It was a struggle to obtain following grants for such a radical departure from the established approaches, the research crowdfunding efforts didn’t go that well (as is usually the case – it is very hard to crowdfund scientific research), the researchers involved moved on, the institutions involved abandoned any effort to maintain and license the intellectual property. All of this happens to many projects in the research community, year after year, regardless of their scientific merits and potential to produce viable, useful therapies.

Sadly, intellectual property is such a linchpin in the standard approach to biotechnology investment, as well as in Big Pharma business models, that technologies in the public domain tend to be left for dead. The view is that no-one can monopolize them, own that whole part of the field, which is seen as necessary in order to justify the enormous resources needed to push a therapy through the present heavy-handed regulatory system. Yet it is nonsense to think that any approach to therapy can in practice be monopolized. Every successful development program quickly results in other organizations putting significant efforts into finding ways to achieve a similar result via the same mechanism that nonetheless bypass existing patents. Still, near all investors and institutions in the commercial space steer clear of public domain science until such time as someone produces clinical success by doing otherwise.

Thankfully, the Kimer Med team are willing to be outliers in this matter. They have picked DRACO as their cause to champion, and intend to raise funds to replicate the work, expand it, and bring this radical new approach to antiviral therapy to the clinic. To the degree that they achieve success, others will follow.

We Should Actually Try to Treat Aging for a Change

I am generally in favor of the sentiment offered in this commentary on recent clinical trial failures for the first attempts to guide anti-aging technologies through the FDA gauntlet, which is that researchers and developers should be aiming to treat aging, not specific age-related diseases. There is likely to be a greater incidence of failure on the way to the clinic, and for entirely avoidable reasons, if everyone is attempting to force a more or less square peg into a more or less round hole.

Longevity trials: time to change the approach?

Following the recent clinical trial failures by Unity Biotechnology and resTORbio, Buck Institute professor Brian Kennedy feels that a change in approach is potentially needed. “I get the idea that you target aging pathways, but then you try to treat disease because you need to get FDA approval and reimbursement from insurance companies – but if that strategy doesn’t work, we’ve got to stop doing it. I think we should actually try to treat aging for a change.”

While Kennedy agrees that effort needs to continue to convince the FDA to recognise aging as a treatable disease, Kennedy also believes that there are alternative approaches that can be employed. “You don’t need the FDA to approve your trial, you need an institutional review board to approve your trial. From an academic standpoint, as long as you can convince people that the trial is safe, you can use biomarkers and study the effects of these drugs. So I think if we start generating that kind of data, then it’ll be a lot easier to get the FDA on board, and hopefully the rest of the world on board. We need to nail down the foundation here and stop giving people excuses why this won’t work. I’m still optimistic about drugs, but if you develop a drug for A and try to treat B, and then you wonder why it doesn’t work – I’m starting to feel like the strategy may not work that well.”

Of course, if companies are going to run trials on aging, then a clearer consensus is needed on the definition of aging, and Kennedy is encouraged by developments in the various clocks that measure biological age. “There’s a bunch of clocks and we don’t really know how they relate to each other yet, and how specific clocks relate to specific kinds of age-related disease. There are a lot of questions to answer, but I think that the most advanced clocks are starting to look like good biomarkers. Some may be better than others but I’m very optimistic about these biomarkers.”

At present the FDA doesn’t recognize aging as a condition that can be treated, so the first generation of companies working on therapies that target mechanisms of aging will all attempt to apply their approach to specific age-related conditions. If successful, the vast majority of usage will then be off-label, as physician networks apply the therapy at their judgement, based upon the extensive literature suggesting that it will be effective for many age-related conditions. It is in the arena of widespread off-label use that the real battle to lighten the regulatory burden will take place. While off-label use is entirely legal, the FDA will likely attempt to shut down providers and manufacturers, in order to force further trials when a therapy becomes widely used in this way.

It would be much easier if we could all just obtain clinical approval by directly assessing the impact of a potential rejuvenation therapy on aging. Or better, obtain clinical approval by demonstrating safety only, rather than safety and efficacy as presently required by the FDA, and letting later studies, reviews, and the marketplace sort out what actually works. It would also be much easier if the FDA was not the bureaucratic monstrosity that it presently is, operating under perverse incentives that cause regulators to have more than doubled the cost of compliance in the past twenty years, at the same time as reducing the number of new therapies that arrive on the marketplace. I don’t see any of this changing any time soon, however. Which is why we will continue to see companies in the longevity industry applying their therapies to specific age-related conditions in order to obtain regulatory approval.

As a sidebar, the trial failures in question were those of UNITY Biotechnology, for senolytics versus knee osteoarthritis, and resTORbio, for an mTORC1 inhibitor versus influenza risk in the elderly. In the former case, the present consensus among observers is that UNITY took a risk on localized senolytic treatment being good enough, and has demonstrated that it isn’t. Senescent cells are present throughout the body, and the inflammatory signals that they generate circulate widely. For an inflammatory joint disease, the background inflammation may well be more relevant in many individuals than the local inflammatory process of joint tissue. In the case of resTORbio, the whisper mill suggests that they were tripped up by a change to the trial endpoint forced on them by the FDA between phase 2 (successful) and phase 3 (failure). Equally, one might suspect that the effect sizes for mTOR inhibition on the immune system are just not that large or that reliable in a general population of humans – this may well be the case for all approaches derived from calorie restriction and stress response upregulation research. We shall see.

Connecting the Immune Response to Amyloid-β Aggregation in Alzheimer’s Disease via IFITM3

It is well established that chronic inflammation in brain tissue contributes to the onset and progression of neurodegenerative conditions such as Alzheimer’s disease. Short-term inflammation is a necessary part of the response to injury and infection, required to mobilize immune cells. Inflammation that fails to resolve and continues unabated for the long term is disruptive to tissue function, however, and very definitely harmful. Unfortunately, aging is characterized by progressively increasing chronic inflammation, the result of processes such as accumulation of senescent cells and harmful metabolic byproducts.

Alzheimer’s is a complicated condition. It is thought to begin with a slow aggregation of amyloid-β deposits over the course of years. This produces mild cognitive impairment and a state of chronic inflammation sufficient to trigger a later, much more harmful aggregation of altered tau protein. This later stage leads to dementia and death. Clearing amyloid-β from the brain hasn’t produced meaningful benefits to patients, however, suggesting that it is not the key process in the development of the condition.

An alternative view of Alzheimer’s disease is that persistent infection causes both chronic inflammation and amyloid-β aggregation, as amyloid-β is actually a part of the innate immune system – an anti-microbial peptide. In this view the more important problem is the chronic inflammation of aging, the constant over-activation of the immune system in brain tissue. The best targets for treatment are thus the set of mechanisms that produce that inflammation, such as senescent cell accumulation, the presence of persistent pathogens such as herpesviruses, and so forth. Supporting evidence is emerging for this position, such as today’s research materials, in which the immune response is linked to amyloid-β production.

Study Links Inflammation to Alzheimer’s Disease Development

Recent studies have found that beta-amyloid has antiviral and antimicrobial properties, suggesting a possible link between the immune response against infections and the development of Alzheimer’s disease. Researchers have now discovered clear evidence of this link: A protein called IFITM3 that is involved in the immune response to pathogens also plays a key role in the accumulation of beta-amyloid in plaques. IFITM3 alters the activity of an enzyme called gamma-secretase, which chops up precursor proteins into the fragments of beta-amyloid that make up plaques. Researchers found that removing IFITM3 decreased the activity of the gamma-secretase enzyme and, as a result, reduced that number of amyloid plaques that formed in a mouse model of the disease.

Neuroinflammation (inflammation in the brain) has emerged as an important line of inquiry in Alzheimer’s disease research. Markers of inflammation, such as certain immune molecules called cytokines, are boosted in Alzheimer’s disease mouse models and in the brains of people with Alzheimer’s disease. This study is the first to provide a direct link between this inflammation and plaque development – by way of IFITM3.

Scientists know that the production of IFITM3 starts in response to activation of the immune system by invading viruses and bacteria. These observations, combined with the new findings that IFITM3 directly contributes to plaque formation, suggest that viral and bacterial infections could increase the risk of Alzheimer’s disease development. Indeed, researchers found that the level of IFITM3 in human brain samples correlated with levels of certain viral infections as well as with gamma-secretase activity and beta-amyloid production. Age is the number one risk factor for Alzheimer’s, and the levels of both inflammatory markers and IFITM3 increased with advancing age in mice, the researchers found.

The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer’s disease

Innate immunity is associated with Alzheimer’s disease1, but the influence of immune activation on the production of amyloid-β is unknown. Here we identify interferon-induced transmembrane protein 3 (IFITM3) as a γ-secretase modulatory protein, and establish a mechanism by which inflammation affects the generation of amyloid-β.

Inflammatory cytokines induce the expression of IFITM3 in neurons and astrocytes, which binds to γ-secretase and upregulates its activity, thereby increasing the production of amyloid-β. The expression of IFITM3 is increased with ageing and in mouse models that express familial Alzheimer’s disease genes. Furthermore, knockout of IFITM3 reduces γ-secretase activity and the formation of amyloid plaques in a transgenic mouse model (5xFAD) of early amyloid deposition. IFITM3 protein is upregulated in tissue samples from a subset of patients with late-onset Alzheimer’s disease that exhibit higher γ-secretase activity. The amount of IFITM3 in the γ-secretase complex has a strong and positive correlation with γ-secretase activity in samples from patients with late-onset Alzheimer’s disease. These findings reveal a mechanism in which γ-secretase is modulated by neuroinflammation via IFITM3 and the risk of Alzheimer’s disease is thereby increased.

Targeting Cellular Senescence to Heal Non-Healing Wounds

An accumulation of senescent cells takes place throughout the body with age. Cells become senescent constantly, the vast majority as a consequence of hitting the Hayflick limit on replication of somatic cells. In youth, these cells are efficiently removed, either via programmed cell death, or destroyed by the immune system. In later life, removal processes slow down, while the damaged state of tissue provokes ever more cells into becoming senescent. In older people, this imbalance leads to a state in which a few percent of all cells in tissues are senescent at any given time. This is, unfortunately, more than enough to produce sizable consequences to health and mortality. Senescent cells secrete a potent mix of inflammatory and growth signals that disrupt tissue function when present consistently.

Senescent cells do conduct useful, necessary activities in an environment in which they are quickly removed, and their signaling is beneficial in the short term. They assist in aspects of embryonic development, for example. The senescence of damaged and potentially cancerous cells suppresses cancer risk by efficiently removing these errant cells. Then there is the role of senescent cells in wound healing, which is the topic of today’s open access paper. Wound healing captures the two-edged nature of cellular senescence in and of itself: wounds heal more rapidly in young individuals due to the presence of senescent cells. But when senescent cells are present in too great a number, they disrupt the processes of wound healing, and can give rise to non-healing wounds.

Fortunately, advances are being made in the development of therapies to selectively destroy senescent cells, or to suppress at least some of their secreted signals. I think that the former is a better strategy, as cell signaling is a very complex, poorly understood environment with many possible targets. Periodically destroying some fraction of senescent cells in a tissue reduces all of the harmful signaling, not just the part that the research community has mapped and understood. When this approach is applied to non-healing wounds, we might hope to see favorable outcomes.

Senescence in Wound Repair: Emerging Strategies to Target Chronic Healing Wounds

The widespread causative biological effects of cellular senescence in tissue ageing pathology make the therapeutic modulation of senescence an attractive target for a plethora of age-related diseases. Genetic studies positively support this idea, with inducible knockdown of p16 alleviating hallmark features of ageing in progeroid murine models. In fact, the well-documented effects of caloric restriction, which both extends mammalian lifespan and delays the onset of age-related disease, may be a physical manifestation of tissue senescence modulation. Caloric restriction has been shown to reduce cardiac senescence, and senescence in hepatocytes and intestinal crypt cells in vivo.

A considerably more attractive proposition is the use of senescence-targeted drugs, otherwise known as senolytics. These drugs affect unique features of senescent cells, such as resistance to apoptosis. Senescent cells upregulate prosurvival pathways, particularly BCL-2. This opens up drug repurposing opportunities around the numerous BCL-2 inhibitors that were developed for the treatment of cancer. Results have been promising. Targeting BCL-2 in vivo induces apoptosis and thus eliminates senescent cells in the lung following irradiation and throughout the body following irradiation or natural ageing.

Other senolytics that have demonstrated experimental efficacy include the tyrosine kinase inhibitor, Dasatinib, used to treat leukaemia, and the flavonoid p53 activator, Quercetin. Combinatorial treatment with Dasatinib and Quercetin extends lifespan, alleviates frailty, and improves vasomotor function in aged mice. Dasatinib and Quercetin have also shown promise in a phase I trial in diabetic kidney disease patients, where reduced senescent cells and circulating SASP factors were observed following administration. Alternative flavonoids are now being tested for their potential senolytic effects, such as Fisetin, which is able to eliminate senescent cells and, crucially, restore tissue function in aged mice.

The importance of transient senescence for effective healing should not be underestimated. As noted previously, temporary induction of senescence aids rapid tissue reformation. During a normal damage response, these senescent cells are effectively cleared by natural killer cells and macrophages. Nevertheless, in chronic situations, senescent cells persist, likely due to elevated immunosenescence and resulting impaired immunological functions. It follows that treatments to boost immune system function, for instance by aiding senescent cell recognition, could be beneficial in the context of transient senescence and tissue repair. Generally, senescent cells express stimulatory ligands that bind to NK2GD receptors on natural killer cells, thus initiating a killing response. However, senescent fibroblasts in aged skin have recently been shown to express HLA-E, which bypasses recognition and clearance by natural killer and T cells. Here, approaches developed in the cancer field may also be useful, for example engineering T cells to express receptors that target specific cellular (tumour) proteins. Studies to identify and validate new senescent cell receptors will be essential to the development and clinical application of such immune-regulated approaches.

We remain a long way from implementing senescence-targeted treatments for pathological wound healing, yet it is reassuring to see that current senolytic drugs display efficacy across a wide range of tissues and pathologies. In a number of studies, systemic senolytic treatments have been shown to have clear effects in peripheral target tissues across a range of treatment regimens. For example, a single dose of BCL inhibitor, and dosing over consecutive days, was able to reverse irradiation-induced senescence in different tissues. In other work, aged mice showed improved physical performance following a biweekly oral treatment of Dasatinib and Quercetin over 4 months, yet reduced SASP was observed in human ex vivo cultured adipose tissue within 48 h of treatment. Moreover, a single 3 day oral treatment of Dasatinib and Quercetin was able to reduce senescence in the adipose tissue of diabetic patients in a phase I trial. These studies therefore suggest that senolytic treatments not only have rapid effects in target peripheral tissues, but can overcome established tissue senescence.

Experimental studies do show beneficial effects of modulating senescence in the skin. For example, elimination of senescent cells from the epidermis restored proliferative capacity in hair follicle stem cells, known to participate in wound healing. Further, blockade of the potential senescence receptor, CXCR2, directly accelerated healing in human ex vivo skin wounds and diabetic murine wounds in vivo. Here, a CXCR2 antagonist was administered to wounds topically (ex vivo) and subcutaneously (in vivo), suggesting direct delivery to the wound site as a viable administration route. Indeed, elevated CXCR2 has previously been observed in diabetic wounds, and more recently in T cells from human diabetic patients. We note with interest that pharmacological inhibition of CXCR1/2 additionally prevents inflammation-mediated damage to pancreatic islets, thus prohibiting streptozocin-induced diabetes in mice. Therefore, CXCR2 appears a common factor in both the ontology and local pathology of diabetes. Senolytics should certainly be considered for the treatment of human chronic wounds characterised by high levels of senescence. However, given that knockdown of CXCR2 and ablation of senescent cells actually delays acute wound healing, future senescence-targeted therapies should be reserved for the treatment of chronic conditions.

Hormone Therapy in Postmenopausal Women Correlates with Lesser Senescent Cell Signaling

Beyond their use for conditions of severe hormone deficiency, hormone therapies are one of the higher profile approaches taken by the less rigorous, more dubious end of the “anti-aging” medical community. An interesting consequence of the greater focus on underlying mechanisms of aging in the research and development community, particularly senescent cell accumulation at the present time, is that scientists and physicians now have access to a novel set of measurements that are definitively connected to aging, and can use those measurements to try to figure out whether any of the overhyped, dubious strategies in the “anti-aging” marketplace are actually doing something useful (even if marginal) under the hood.

Senescent cells secrete a potent mix of inflammatory and other molecules, the senescence-associated secretory phenotype (SASP). This is how a comparatively small number of lingering senescent cells in aged tissues cause harm: their signaling disrupts tissue structure and maintenance, and produces a state of chronic inflammation that drives the onset and progression of many age-related conditions. Over the past few years, the SASP has been far more extensively mapped than was previously the case. Measuring circulating levels of the more prominent SASP molecules is a way to assess the burden of aging, or at least that due to this particular aspect of age.

That is the approach taken in today’s open access paper, in which the authors report that hormone treatment of postmenopausal women is associated with lower levels of some of the SASP factors known to be involved in inflammatory signaling. Whether this reflects a lesser burden of senescent cells, or a reduced signaling of such cells is an open question, though the authors here seem to lean towards the latter possibility, given what is known of the way which estrogen regulates metabolism. In general, hormones have extremely broad effects on metabolism, and it is certainly the case that their use comes with many caveats.

Effect of menopausal hormone therapy on proteins associated with senescence and inflammation

Cell senescence, a state of cell cycle arrest due to the finite capacity of cells to proliferate, also occurs as a result of the accumulation of molecular and cellular damage. Senescent cells secrete an array of cytokines, chemokines, growth factors, and proteases collectively referred to as the senescence-associated secretory phenotype (SASP). The array of SASP proteins includes many proteins that have been shown to be regulated by estrogen and to be secreted by platelets, leukocytes, and vascular endothelium including the metalloproteins (MMPs), tumor necrosis factor-α (TNF-α), ecosinoids, and serotonin. However, other proteins considered to be part of the SASP array (e.g., GDF15, Fas, MIP1α, and TNFR1) may be more specific indicators of the systemic senescent cell burden.

In response to DNA damage, senescence serves as an anticancer mechanism and may also have beneficial functions in embryogenesis, parturition, and tissue repair. However, senescent cells that are not cleared efficiently by the immune system disrupt tissue function, which increases the vulnerability to the onset and progression of a host of age-related diseases, including pulmonary dysfunction, cardiovascular disorders, osteoporosis, neurodegeneration, and diabetes. In part, the deleterious effects of senescent cells are mediated by the SASP. Strategies to remove senescent cells and suppress the SASP are now being pursued as a means to counter age-related diseases and geriatric syndromes.

Estrogen is a steroid hormone implicated in modulating cell senescence. For example, estrogen decreases cell senescence in endothelial progenitor cells, and activates estrogen receptor alpha (ERα) to inhibit cell senescence-like phenotypes in human epithelial cells. Estrogen also slows deficits associated with aging and cell senescence in bone, such as declining bone density. However, little is known regarding how cell senescence might be modified by natural changes in hormone concentrations, such as those that occur during menopause, and how this might be modulated by hormone therapies. This study examined whether menopausal hormone therapies, in the form of oral conjugated equine estrogens (oCEE) and transdermal 17β-estradiol (tE2), altered the circulating levels of a specific set of SASP proteins in women who had undergone natural menopause.

Growth differentiation factor 15 (GDF15), tumor necrosis factor receptor 1 (TNFR1), FAS, and macrophage inflammatory protein 1α (MIP1α) were measured in serum. Results were compared among menopausal women participating in the Kronos Early Estrogen Prevention Study randomized to either placebo (n = 38), oral conjugated equine estrogen (oCEE, n = 37), or transdermal 17β-estradiol (tE2, n = 34). Serum levels of the senescent markers for each treatment were compared to placebo 36 months after randomization. We found that serum levels of GDF15, TNFR1, and FAS, but not MIP1α, were lower in both the oCEE and tE2 groups compared to placebo. Differences in the magnitude of effect of the two active treatments may reflect the differences in circulating levels of estrogen metabolites due to formulation and mode of delivery.

Approaches to Optimize Growth of Muscles in Response to Resistance Training in Old People

Muscle growth in response to resistance exercise is attenuated in older individuals, the result of much the same set of processes that lead to sarcopenia, the name given to the characteristic loss of muscle mass and strength that occurs with age. Resistance exercise is clearly still beneficial in later life, judging by the reduction in mortality risk that results, but can it be made more beneficial? Undoubtedly yes, given the appropriate technology to address the underlying root causes of degenerative aging, but all too few such technologies exist at the present time. The use of senolytic therapies to destroy harmful, inflammatory senescent cells is one of the few such technologies, and a plausible approach to improving muscle function in older people, but alas is not mentioned in this paper. The focus here is instead on established ways to tinker with the operation of metabolism in muscle tissue, with results on muscle growth in response to exercise that tend to be modest at best.

The acute anabolic responses to feeding and exercise were found to be dampened in old subjects compared to their young counterparts, thus limiting their recovery and muscle growth. It has been hypothesized that the blunted increase in protein synthesis following acute muscle loading may influence the smaller gains in lean tissue following resistance exercise training in older adults. As such, supplementation of high-quality protein may improve anabolic response to a single bout of exercise. Specific amino acid supplements are available, in the forms of essential amino acids (EAAs), branched-chain amino acids (BCAAs), and leucine. Leucine-rich EAA supplementation enhanced muscle strength following exercise. It is important to note, however, that prolonged protein supplementation with whey or casein, in the setting of a training program, does not appear to improve the exercise response in elderly patients. β-hydroxy-β-methylbutyrate (HMB), a metabolite of leucine which directly activates mTOR, has also been investigated and increased lean muscle mass and strength in sarcopenic individuals.

Chronic, age-related inflammation in skeletal muscle may play a role in aging-associated muscle loss. NF-κB, a master transcriptional regulator of inflammation, becomes upregulated in skeletal muscle with aging. This has led to investigations of whether NF-κB inhibition using commercially available NSAIDs can improve the maintenance of muscle mass. The efficacy of NF-κB inhibition, using commercially available NSAIDs, on the maintenance of muscle mass and strength in response to exercise has been explored in many clinical studies in elderly patients. A 3-month bout of resistance exercise in elderly patients with knee osteoarthritis, NSAIDs therapy resulted in a mild improvement in muscle strength, however, without hypertrophy. Other studies found that NSAID treatment augmented training-induced improvement in strength with associated muscle hypertrophy and limited muscle catabolism. Others have instead shown that NSAID supplementation does not improve skeletal muscle strength or function during physical training. As such, the use of NSAIDs during exercise remains controversial.

Testosterone has emerged as another potential supplement to exercise for the elderly population. Multiple studies have demonstrated that testosterone levels decrease with age. Testosterone administration to elderly patients increases both muscle mass and maximal voluntary strength in a dose-dependent fashion, possibly by the induction of myogenic gene expression. Despite this assertion, the additional benefits of physiological testosterone replacement in elderly patients remains unclear. A prospective study demonstrated increased upper body strength following testosterone treatment of elderly patients with low to normal serum testosterone, but this treatment did not offer any benefit beyond resistance exercise alone.

The growth hormone (GH) axis is another area that has received attention as a potential supplement for exercise therapy for the elderly. GH is made in the pituitary gland and promotes IGF-1 expression in skeletal muscle. IGF-1, in turn, stimulates the Akt/mTOR pathway which promotes muscle anabolism and protein synthesis in response to exercise. In elderly patients, GH treatment increases lean body mass and decreases fat-to-muscle ratio from baseline, although it is unclear as to whether this was attributable to increased skeletal muscle mass. However, multiple studies have shown that healthy elderly patients do not see any additional benefit in strength or muscle hypertrophy with GH supplementation as compared to exercise alone, even at 6-month follow-up. Despite the integral role of the GH/IGF axis on muscle development or hypertrophy, it does not appear to have a therapeutic benefit in physical training in healthy individuals.

HDAC9 Inhibition Slows the Progression of Osteoporosis in Old Mice

Researchers here explore a role for HDAC9 in the progression of osteoporosis, the progressive loss of bone density with age. The signs suggest that age-related upregulation of HDAC9 is involved in cellular senescence and the disruption of cell populations responsible for creating bone tissue. Bone tissue is constantly remodeled, created by osteoblast cells and destroyed by osteoclast cells. The proximate cause of osteoporosis is that the activity of osteoclasts comes to outweigh that of osteoblasts, removing bone structure faster than it is deposited. Many mechanisms that might contribute to this imbalance have been investigated over the years, but it remains unclear as to how exactly they all fit together, and which are the most important.

Osteoporosis is a common aged-related disease and is characterized by decrease bone mass and bone mineral density, leading to bone fragility and a higher risk of fractures. Researchers have discovered several risk factors associated with osteoporosis, including genetic and epigenetic factors, hormone imbalance, and stem cell senescence. Bone marrow mesenchymal stem cells (BMMSCs) are a group of cell residual in the bone marrow. They have self-renewal capacity and multilineage differentiation potential. There is considerable data showing that BMMSCs play crucial roles in maintaining bone remodeling, reparation, and regeneration. Importantly, the number of BMMSCs declines and their lineage commitment shifts from osteoblasts to adipocytes with aging leading to an imbalance between bone mass and bone marrow fat. This imbalance is considered to be a hallmark of aged-related bone loss disorder, osteoporosis.

During senescence, mesenchymal stem cells (MSCs) undergo epigenetic and transcriptional changes, including decreased expression of stemness genes, Oct4 and Nanog, and increased age-related genes, p16 and p53. Some adverse factors that trigger MSC senescence have been identified, such as reactive oxygen species (ROS) accumulation, telomere shortening, and epigenetic effectors, including histone deacetylases (HDACs) and DNA methyltransferases (DNMTs). However, the details of the epigenetic regulation network remain elusive and its roles in BMMSCs during aged-related bone loss remain to be established.

HDACs are important epigenetic regulators that control gene transcription by removing acetyl groups. In this study, we report that HDAC9 plays an important role in maintaining the balance between osteogenesis and adipogenesis of BMMSCs during aged-related bone mass loss. Furthermore, we found that the downregulation of HDAC9 could partially reverse the differentiation of aging BMMSCs and bone loss in mice by regulating autophagy. These results suggest that aged-related bone mass loss may be partially controlled by the HDAC9-meditated autophagy of BMMSCs.

Raised Blood Pressure is So Harmful that Reductions are Beneficial Even Without Addressing Underlying Causes

The raised blood pressure of hypertension causes harm throughout the body, raising mortality risk and accelerating the onset and progression of numerous forms of ultimately fatal age-related disease. It accelerates atherosclerosis, and raises the risk of a fatal rupture of blood vessels weakened by atherosclerotic lesions. It causes pressure damage to delicate tissues throughout the body. It leads to detrimental remodeling of heart tissue and the onset of heart failure. Thus forcing a reduction in blood pressure is quite beneficial in later life, even when it is achieved – as is presently the case – by overriding regulatory mechanisms, without addressing any of the underlying forms of cell and tissue damage that produce hypertension. Imagine how much better the outcomes could be if those forms of damage were addressed, reducing not only hypertension but many other forms of downstream harm.

Blood pressure medication can prevent heart attacks and strokes – even in people with normal blood pressure. “Greater drops in blood pressure with medication lead to greater reductions in the risk of heart attacks and strokes. This holds true regardless of the starting blood pressure level, in people who previously had a heart attack or stroke, and in people who have never had heart disease.”

There has been controversy about whether pharmacological blood pressure lowering is equally beneficial in people with versus without a prior heart attack or stroke, and when blood pressure is below the threshold for hypertension (typically 140/90 mmHg). Evidence from previous studies has been inconclusive, leading to contradictory treatment recommendations around the world. This was the largest – and most detailed – study ever conducted to examine these questions. The researchers combined data on individuals who had participated in a randomised clinical trial and conducted a meta-analysis. The study included 348,854 participants from 48 trials.

Participants were divided into two groups: those with a prior diagnosis of cardiovascular disease and those without. Each group was divided into seven subgroups based on systolic blood pressure at study entry (less than 120, 120-129, 130-139, 140-149, 150-159, 160-169, 170 and above mmHg). Over an average four years of follow-up, each 5 mmHg reduction in systolic blood pressure lowered the relative risk of major cardiovascular events by about 10%. The risks for stroke, ischaemic heart disease, heart failure, and death from cardiovascular disease were reduced by 13%, 7% and 14% and 5%, respectively. Neither the presence of cardiovascular disease nor the level of blood pressure at study entry modified the effect of treatment.

Mechanisms by which Hearing Loss Might Contribute to the Onset of Dementia

There is a correlation between age-related hearing loss and cognitive decline. Is this because similar mechanisms of cell and tissue damage disrupt both the function of the brain and nerve cells in the ears, or is this because hearing is important in the ongoing operation of the brain? Supporting evidence exists for both options. Here, researchers discuss ways in which loss of hearing might disrupt brain function.

Hearing loss in midlife has been estimated to account for 9% of cases of dementia. Acquired hearing loss is most commonly caused by cochlear damage, while dementia is due to cortical degeneration that typically begins in multimodal cortex. This immediately begs the question of how the two are linked. This is a crucial question from a theoretical perspective, as there are multiple biological and psychological pathways that may link peripheral auditory function to broad-based cortical changes associated with dementia. It also has critical practical implications because while it is difficult, if not impossible, to remediate cortical degradation, hearing loss is widely treatable with hearing aids or cochlear implants. Thus, an understanding of the mechanisms linking the two could have wide-ranging public health importance.

There are a number of possible mechanisms for the relationship between hearing loss and dementia. A first possible mechanism is common pathology affecting the cochlea and ascending auditory pathway (causing hearing loss) and the cortex (causing dementia). Alzheimer’s disease (AD)-related pathology has been observed in the retina, but it is not well established as occurring in the cochlea. Transgenic mouse models of AD suggest that AD may be associated with cochlear pathology and hearing loss, but the loss is early onset, unlike the midlife impairment in humans. Vascular pathology can also occur in the cochlea, and this is one of the factors implicated in typical acquired hearing loss. It can also affect the ascending auditory pathway and auditory cortex. Vascular mechanisms are therefore potential contributors to the hearing loss associated with cases of vascular dementia.

A second possible mechanism is that hearing loss leads to the decreased stimulation of cognitive processing. The idea is that auditory deprivation creates an impoverished environment, particularly with the diminishment of speech and language input, that negatively affects brain structure and function. This change in brain structure and function is a risk factor for the subsequent development of dementia. A variety of lines of evidence suggest that listening experience may have a direct impact on the human brain. In parallel to the enriched environment studies with mice, the active listening experience of musicians is associated with positive effects on the structure of auditory cortex and the hippocampus and functional changes in the hippocampus. Piano tuners, expert listeners who spend large amounts of time carrying out a highly specialized form of selective listening, demonstrate hippocampal structural correlates of that experience.

A third mechanism is based on the idea that people with hearing impairment use greater cognitive resources for listening, making these resources unavailable for other aspects of higher cognition when they are “occupied” during listening. “Resources” refers here to the means for cognitive tasks such as attention, working memory, or language processing. There is debate about how cognitive resources are allocated, and the corresponding neural bases. With respect to working memory, for example, there is a question about the extent to which resources may be specifically allocated to objects or represent a distributed resource. Further debate concerns the extent to which working memory resources reflect neuronal or synaptic mechanisms, or both. What is important here, however, is that there is a fixed capacity for many general cognitive operations. These resources may be absorbed when listening becomes challenging, reducing their availability for other aspects of cognition.

A fourth possible explanation focuses on auditory cognitive mechanisms in the medial temporal lobe (MTL) that may be specifically linked to AD pathology in the same region. Although MTL structures are not classically regarded as part of the auditory system, animal models support their role in auditory processing. This mechanism starts from the same idea as the prior mechanism, that hearing loss alters cortical activity, including in the MTL. The critical difference is the incorporation of an interaction between that altered activity and AD pathology. The AD pathology that best correlates with the cognitive phenotype is neurofibrillary change related to tau pathology. The earliest neurofibrillary changes in typical AD are found in MTL structures, particularly the perirhinal cortex, which has a strong functional relationship to the hippocampus. This raises the possibility of an interaction between this pathological process and changes in neuronal activity in MTL structures that occur in hearing impaired individuals.

An Interview with a Principal Investigator at Calico

Calico is Google’s venture into aging research. It has, in general, been a disappointment to the community – though I suspect that this is a matter of unrealistic expectations as to the path that any new, large deployment of capital is likely to follow. Rather than taking on any of the approaches to rejuvenation that might plausibly produce sizable gains in life span, such as those of the SENS portfolio, Calico has focused on very staid, long-standing metabolic manipulations derived from the study of calorie restriction and growth hormone loss of function mutants. These lines of research are highly unlikely to produce sizable gains in health and longevity in humans, as the calorie restriction response and disruption of growth hormone metabolism are known to produce only modest gains in our species. Calico, like the Ellison Medical Foundation that preceded it, has in essence become a small arm of the National Institute on Aging, characterized by conducting fundamental rather than translational research, and in areas of the field that won’t do much for human health and life span at the end of the day.

What area of aging and age-related diseases has Calico’s biggest focus at the moment?

Our top-level goal is to develop interventions that delay aging, but to test such interventions, we have to be able to measure aging. This is easier said than done – the gold standard, lifespan, takes a long time and is relatively information-poor. There are molecular and cellular changes that occur with age, but it’s not always clear which are the most relevant readouts. We’d like to measure aspects of physiological decline, but current healthspan assays take a lot of time and effort, and even then tend to be pretty noisy. To address those limitations, we’ve spent a lot of time developing innovative tools and novel analyses for quantifying physiological decline in mouse models. We emphasize automated, longitudinal monitoring and multi-dimensional time-series analysis.

On the intervention side, one area of focus for my lab is IGF signaling. This was a pretty straightforward choice – reduced IGF signaling is the most validated anti-aging intervention known (slows aging from worms to mammals, with the largest effect sizes ever reported). There are challenges with targeting this pathway, of course – dose-limiting toxicity, endocrine feedback, lack of biomarkers, just to name a few – but we think we’ve identified a viable therapeutic strategy.

What emerging discoveries and techniques is Calico utilising?

I’m excited about using outbred mice for intervention testing. We’re clearly not the first people to think of this, but we’ve embraced the concept. Outbred mice are somewhat more resource-intensive than inbred mice because they have more variability, but we think they’re worth it. As we’re all painfully aware, many published results fail to replicate. I think that a big fraction of what’s being called irreproducibility is actually a lack of generalizability. In other words, the results might repeat under the exact same conditions, but alter those conditions just a little and it’s a different answer. For mouse studies, strain background is an important condition, and we worry about results from a single, homozygous-at-all-loci genotypes not being generalizable. Outbred mice help us avoid this

What do you think is the best way to quantify longitudinal decline – are there key biomarkers that you’re addressing?

Aging manifests at all levels of biological organization (i.e. molecules, cells, tissues, organs, organ-systems, and whole organisms), and measuring aging at each level has pros and cons. Molecular and cellular data provide mechanistic insight and can point to new therapeutic targets, but it can be hard to know if effects are truly relevant to the organism (e.g. does delaying mutation accumulation delay decline in organ function)? Organ-level and physiological data provide health relevance, but it can be hard to tease out mechanism – good for testing putative targets, less good for target discovery. My lab focuses on developing tools for measuring organism-level decline because we think the state of the art is lacking and robustly testing putative targets is rate-limiting in the field.

Long Lived Humans Do Not Exhibit Fewer Harmful Gene Variants

Why are long lived humans long lived? Why does this trait often run in families? One of the few firm advances in answering these questions is to rule out the hypothesis that long-lived lineages bear fewer detrimental gene variants. Several studies and study populations have indicated that there are just as many harmful variants present in the genomes of exceptionally long-lived people as are present in the rest of us. Beyond that, it remains to be seen as to just how much of exceptional longevity is in fact genetic. Broader genetic studies have in recent years continued to revise downward the contribution of genetics to variation in human life span. At the present time, it appears to be almost entirely a matter of lifestyle choice and environmental exposures to infectious disease, particulate air pollution, and so forth.

Centenarians (exceptionally long-lived individuals – ELLI) are a unique segment of the population, exhibiting long human lifespan and healthspan, despite generally practicing similar lifestyle habits as their peers. We tested disease-associated mutation burden in ELLI genomes by determining the burden of pathogenic variants reported in the ClinVar and HGMD databases using data from whole exome sequencing (WES) conducted in a cohort of ELLI, their offspring, and control individuals without antecedents of familial longevity (n = 1879), all descendent from the founder population of Ashkenazi Jews.

The burden of pathogenic variants did not differ between the three groups. Additional analyses of variants subtypes and variant effect predictor (VEP) biotype frequencies did not reveal a decrease of pathogenic or loss-of-function (LoF) variants in ELLI and offspring compared to the control group. Case-control enrichment analyses of pathogenic variants conducted in ELLI and controls also did not identify significant differences in any of the variants between the groups and polygenic risk scores failed to provide a predictive model. Interestingly, cancer and Alzheimer’s disease-associated variants were significantly depleted in ELLI compared to controls, suggesting slower accumulation of mutation. That said, polygenic risk score analysis failed to find any predictive variants among the functional variants tested.

The high similarity in the burden of pathogenic variation between ELLI and individuals without familial longevity supports the notion that extension of lifespan and healthspan in ELLI is not a consequence of pathogenic variant depletion but rather a result of other genomic, epigenomic, or potentially nongenomic properties.

A Meta-Analysis of the Ability of Exercise to Reduce Age-Related Mortality

Exercise improves health, and that statement continues to be the case throughout life, even into late old age, and while suffering from age-related conditions that impact the ability to exercise. Exercise exhibits a dose-response curve, just like any other intervention to improve health. More is better for near all people: one has to undertake a great deal of physical activity indeed to come to the point of diminishing returns or self harm. One of the interesting findings of the past twenty years, achieved after it became cost-effective to measure activity more precisely via the use of wearable accelerometers, is that even very modest levels of exercise make a sizable difference to mortality rates in older people. Becoming sedentary is a fate to be avoided.

The current evidence for the general population regarding physical activity and mortality is comprehensive and unambiguous. Numerous large cohort studies have consistently demonstrated an inverse relationship between physical activity levels and mortality. Compared with the lower physical activity groups, the risk of premature death was remarkably reduced in the higher physical activity groups. One meta-analysis revealed that per 1 hour increment of moderate-intensity physical activity per week, the relative risk of mortality was reduced by 4%.

In the updated physical activity guidelines for healthy adults from the U.S. Department of Health and Human Services, a clear dose-response association between the volume of physical activity and mortality rates has been shown. The shape of the dose-response curve is characterized by a regressive, non-linear effect, where the greatest difference in mortality rates occurs among inactive and minimally active individuals. For higher physical activity levels, the dose-response curve flattens out. This means that the relative risk of mortality continues to decline with higher volumes of physical activity with no adverse effects on mortality, even at very high levels of physical activity.

The objective of this study was to conduct a systematic review and dose-response meta-analysis of physical activity and mortality in people with selected non-communicable diseases (NCDs). We aimed to define the dose-response relationship between post-diagnosis physical activity and mortality rates for nine NCDs with a high global burden of disease, including low back pain, type 2 diabetes (T2D), osteoarthritis, depressive disorder, chronic obstructive pulmonary disease (COPD), breast cancer, lung cancer, stroke, and ischemic heart disease (IHD).

In total, 28 studies were included in the meta-analysis: 12 for breast cancer, 6 for type 2 diabetes, 8 for ischemic heart disease and 2 for COPD. The linear meta-analysis revealed that each 10 metabolic equivalent task hours increase of physical activity per week was associated with a 22% lower mortality rate in breast cancer patients, 12% in ischemic heart disease patients, 30% in COPD patients, and 4% in type 2 diabetes patients. There was indication of a non-linear association with mortality risk reductions even for low levels of activity, as well as a flattening of the curve at higher levels of activity. Thus higher levels of post-diagnosis physical activity are associated with lower mortality rates in breast cancer, type 2 diabetes, ischemic heart disease, and COPD patients, with indication of a no-threshold and non-linear dose-response pattern.

A Damage-Based View of Aging, Offering the Hope of Rejuvenation through Repair

This paper, published earlier in the year, is a reaffirmation of the consensus position that aging is caused by the accumulation of cell and tissue damage, made at a time in which programmed aging theories are becoming more popular. Initiatives such as those of and other groups, in which cells are at least partially reprogrammed towards a pluripotent state in living animals, have spurred greater interest in the characteristic epigenetic changes that take place with aging. That reversing those epigenetic changes produces rejuvenation by many measures is interesting and promising, but it isn’t clear that it can be taken as evidence that epigenetic programs of change are at the root of aging. We might look instead at the evidence for detrimental epigenetic change in cells throughout the body to be an unfortunate consequence of the processes of DNA double strand break repair, for example. If confirmed, that puts age-related epigenetic change firmly in the category of damage, not a program that exists independently of damage as a root cause of aging.

Aging is an irreversible process, and most organisms can never escape the diversity and accumulation of damage that their own functions generate. To reduce damage, species with a simple organization may opt to discard some damage with a part of the cytoplasm, but this mechanism needs to be investigated in more complex species. Interventions such as parabiosis may partially restore aged organ functions through transfusion of young blood to an old organism. This may be considered as a damage dilution process, where the old blood is diluted by the less damaged young blood. It was shown that, following hematopoietic stem cell transfer, the blood of the recipient follows the epigenomic age of the donor, suggesting a possibility to consistently generate younger blood than the actual age of the organism, if the source of hematopoietic stem cells is a young donor. It is important to emphasize that the transition to a younger age, based on one or more tissues being younger than the rest and younger than the chronological age, does not necessarily mean a longer lifespan for the subject, particularly if the lifespan is limited by a particular dysfunction or disorder that causes death.

Although somatic aging appears at first sight irreversible, we cannot bypass the fact that it is successfully reset to zero from generation to generation, suggesting that, during germline development, embryonic development, or some other phases of life there is a process that rewinds the aging clock. Somatic cell nuclear transfer shows that this rewinding process can be also induced in differentiated cell nuclei. These mechanisms of dilution or repair of damage are currently unclear, although evidence suggests that they may involve a combination of cell division, cell selection, epigenetic remodeling, and global activation of genes, especially those genes for controlling DNA damage. These mechanisms allow cells to dilute even the scarcest molecular species such as functionally abnormal RNA, proteins, harmful metabolites, and those that would not be sensed by a cell. Thus, a combination of cell growth, selection, and proliferation dilutes mild damage, in addition to the removal of damage through specialized detoxification, repair, excretion, preemption, and other approaches. These mechanisms together allow the cells to keep the damage in control.

It should be noted that division and dilution are not necessarily related in the context of proliferation of differentiated somatic cells, as, unlike germ cells or stem cells, these cells may undergo senescence or tumor transformation when proliferating in culture. This suggests that there is a particular relationship between cell division and damage dilution, whose mechanism is not yet understood. We think that this relationship is reflected, for instance, in the differences between early embryonic and aged cells, partially due to their different differentiation states. The former may stay in quiescent stage to avoid further damage or proliferate to select the cells with less damage. Compared to adult cells, embryonic cells specifically experience two waves of global demethylation and re-methylation, establishing the same DNA methylation pattern for every generation. These differences suggest a possibility that certain embryonic cells and somatic cells have different modes and rate of damage accumulation and dilution through proliferation. From the damage perspective, the proliferation of cells with more specialized functions bears higher damage, as more specialized molecules are produced, allowing more side-products to be generated. Furthermore, adult stem cells may overcome the proliferation limit when exposed to a mixed pro-stemness signal. This shows that the combined effect of niche pathways that promote the stemness of the adult stem cells may act similarly to reprogramming. Thus, the difference in the damage accumulation between somatic cells and stem cells may lie, at least in part, in the cell matrix environment in which cells reside. Moreover, the environment may undergo a transition to sacrifice stemness for specific biological functions.

To visualize this stage-shifting concept, we advance a weight-scale metaphor, which we call a “stemness-function” model. We designate the two states as “pro-stemness” and “pro-function” based on the balance between damage production and its removal by proliferation and apoptosis. During early life, organisms remain in a “pro-stemness” state, encouraging cells to proliferate and grow so that the damage is unchecked and does not cause cell cycle arrest. In that state, although stem cells exhibit a limited intrinsic immune function, the function to recognize “self” and “nonself” is not yet fully developed, allowing a lower level of inflammation and an increased potential for regeneration. In contrast, in somatic cells, the damage generation can be sensed easier, triggering the reactions such as the DNA damage repair process, growth arrest, apoptosis, and immune responses. Therefore, organisms must undergo a transition from the “pro-stemness” to “pro-function” states, wherein differentiation and specification of cells are supported. Following this transition, the cells enhance their function in reproduction, damage sensing and apoptosis pathway, complete the immune function, and increase fitness by generating specific biological products related to their functions, while adult stem cells at this stage undergo gradual exhaustion. At this stage, damage accumulation is spontaneous while damage dilution via proliferation is not supported in most cell types. During the process of fertilization or before/after it, this damage gets thoroughly checked, cleared and diluted by the transition to the “pro-stemness” state.

What perturbations might then be expected to delay or reverse aging? If a mild “pro-function” feature is induced in the cells with the “pro-stemness” state, it may extend lifespan as we learn from mild overexpression of certain tumor suppressors. Similarly, the weakened immune system upon rapamycin treatment provides an example that the opposite may also work. On the other hand, if a specific function (supported by a certain gene) that shifts the system toward the “pro-function” state is introduced, it may lead to death or premature aging, caused by a sudden increase in function and damage. This might be the case when tumor-suppressor Tp53 is overexpressed in mice, and the animals show a significantly shorter lifespan. It should be noted, however, that similar cases of Tp53 overexpression in mouse models show an indistinguishable lifespan. Nevertheless, considering that cancer-related deaths are more common in lab mice than in humans and that these risks are limited in these cancer-resistant mouse models, there is still a possibility that the overexpression accelerates aging. Conversely, if a “pro-stemness” signal introduced to cells in the “pro-function” state, it may also cause deleterious effects, resulting in cell death or aberrant immortality. For instance, forcing cell proliferation by expressing oncogenes in fibroblasts promotes tumor transformation.

Greater Fitness Correlates with Lower White Matter Hyperintensity Volume in the Aging Brain

White matter hyperintensities in the brain are small areas of damage most likely produced by the rupture or other loss of integrity of tiny blood vessels. In effect they are miniscule strokes, individually unnoticed, but collectively a form of damage to the brain that adds up over time. Since white matter hyperintensities are connected to vascular health, it isn’t too surprising to see that old people possessed of better vascular function, as a consequence of maintaining physical fitness into later life, exhibit a lower burden of this form of damage in the brain. It should be expected that this lesser degree of structural damage contributes to the slower cognitive decline that accompanies higher levels of fitness in later life.

White matter (WM) hyperintensities (WMHs) are one of the most ubiquitous age-related structural changes observed via MRI, yet they are of unknown etiology. WMHs are presumed to be a consequence of age-related vascular changes. Arterial stiffness is associated with WMHs and is the most influential hemodynamic factor in individuals over the age of 60. Age-related arterial dysfunction is the result of a variety of deleterious changes that include intimal remodeling, increased arterial stiffness, and endothelial dysfunction. Age-related changes in the physical properties of, and the interaction between, macrovasculature and microvasculature contribute to the development of WMHs. For example, large artery stiffening transmits increases in pulsatility, the variation of blood pressure throughout the cardiac cycle, to small cerebral vessels. Excessive pulsatility to small cerebral vessels is associated with WMHs.

While cerebrovascular changes are endemic to aging, older adults show considerable variability in vascular brain health. One variable known to positively impact the brain’s vascular health is cardiorespiratory fitness (CRF), a product of regular exercise. However, little is known about the effects of CRF on WMH volume per se. In contrast, higher CRF has been linked to higher WM microstructure in older adults. Since low WM microstructure in normal appearing WM precedes conversion to WMHs, WMHs may also be positively influenced by high CRF. If so, CRF may attenuate the development of WMHs in older adults.

This study explored the effects of CRF on WMH volume in community-dwelling older adults. We further tested the possibility of an interaction between CRF and age on WMH volume. Participants were 76 adults between the ages of 59 and 77 who underwent a maximal graded exercise test and structural brain imaging. Results indicated that age was a predictor of WMH volume. However, an age-by-CRF interaction was observed such that higher CRF was associated with lower WMH volume in older participants. Our findings suggest that higher levels of aerobic fitness may protect cerebrovascular health in older adults.

Dysfunction of the Blood-Brain Barrier as an Early Stage in the Progression to Dementia

The blood-brain barrier is a lining of specialized cells that surrounds blood vessels passing through the brain. The barrier permits only certain molecules and cells to pass, isolating the tissue environment of the brain from that of the result of the body. When the blood-brain barrier leaks, an immediate consequence is inflammation in brain tissue, the result of the brain’s immune cells reacting to the presence of inappropriate molecules. Unfortunately the integrity of the blood-brain barrier degrades with age and the accumulation of molecular damage, as is the case for all other tissues. The resulting inflammation is an important mechanism in the progression towards neurodegenerative disease and dementia. As noted here, degradation of the blood-brain barrier may also prevent necessary molecules from being transported into the brain in sufficient amounts. That also may be an important early determinant of loss of function in brain tissue.

The vascular endothelium in the brain is an essential part of the blood-brain-barrier (BBB) because of its very tight structure to secure a functional and molecular separation of the brain from the rest of the body and to protect neurons from pathogens and toxins. Impaired transport of metabolites across the BBB due to its increasing dysfunction affects brain health and cognitive functioning, thus providing a starting point of neurodegenerative diseases.

The term “cerebral metabolic syndrome” is proposed to highlight the importance of lifestyle factors in neurodegeneration and to describe the impact of increasing BBB dysfunction on neurodegeneration and dementia, especially in elderly patients. If untreated, the cerebral metabolic syndrome may evolve into dementia. Due to the high energy demand of the brain, impaired glucose transport across the BBB via glucose transporters as GLUT1 renders the brain increasingly susceptible to neurodegeneration. Apoptotic processes are further supported by the lack of essential metabolites of the phosphocholine synthesis.

In Alzheimer’s disease, inflammatory and infectious processes at the BBB increase the dysfunction and might be pace-making events. Chronic inflammatory processes of the BBB transmitted to an increasing number of brain areas might cause a lasting build-up of spreading, pore-forming β-amyloid fragments explaining the dramatic progression of the disease.