Fight Aging! Newsletter, June 18th 2018

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • Alzheimer's Disease is More than a Matter of Amyloid and Tau Aggregation
  • Juvenescence Invests in AgeX Therapeutics
  • Greater Fitness and Blood Vessel Elasticity Correlates with Slower Cognitive Decline
  • Clearance of Senescent Cells as a Therapy for Age-Related Muscle Loss and Frailty
  • Not Everyone Feels the Urgent Need for Therapies to Treat Aging, and this is a Sizable Divide in our Broader Community
  • Evolution of Varied Life Spans without Antagonistic Pleiotropy
  • Leukotriene Inhibition Reverses Tau Aggregation and Neuroinflammation in Mice
  • The LEAF Rejuvenation Roadmap
  • For Many People, a Sizable Fraction of Age-Related Hypertension is Self-Inflicted
  • A Reminder that Excess Visceral Fat is Harmful
  • How α-Synuclein Aggregration Kills Neurons in Parkinson's Disease
  • Early Signs of Neurological Damage Observed in Hypertensive Individuals
  • How Amyloid Disrupts Synaptic Plasticity in Alzheimer's Disease
  • Healthy Aging is an Oxymoron
  • B Cells May Drive Harmful Inflammation Following Heart Damage

Alzheimer's Disease is More than a Matter of Amyloid and Tau Aggregation

The open access paper I'll point out today makes the case for raising the profile of mechanisms other than protein aggregation in neurodegenerative conditions. The authors focus on Alzheimer's disease, characterized by the aggregation of amyloid and tau in the brain, but the argument works just as well for most other forms of age-related dementia. That Alzheimer's disease is the result of multiple mechanisms, each of which contributes to pathology to a similar degree, is one of the better explanations for the ongoing failure of clinical trials that focus solely on amyloid clearance. One only has to look at the sizable fraction of Alzheimer's patients who are also diagnosed with vascular dementia to suspect that something of this nature might be an issue. If there are, for example, five important and somewhat independent mechanisms driving a specific medical condition, then the positive outcomes that result from partially addressing just one of those mechanisms may well get lost in the noise.

This class of issue is in fact endemic in attempts to interfere in the pathology of age-related disease at points that are distant from the root causes. The root causes of aging are limited in number, but spread out into a complex tree of descendant forms of damage and reactions to damage. If the approach to medicine takes the form of pruning the outer branches, as it were, then many of those branches (a) represent smaller individual contributions to dysfunction, and (b) are to some degree independent of one another. But further back towards the roots, an intervention might be much more effective, as it targets a form of damage that drives all of the smaller, downstream branches of damage and dysfunction.

That is the simple idealized model, and it is a very useful guide to thinking about strategy in medical research and development. Nothing is that neat and tidy in reality, sadly. Alzheimer's is a complex mix of what we might think of as fundamental damage, such as protein aggregation, and downstream changes resulting from many other forms of molecular disarray, such as inflammation and general vascular dysfunction. It all interacts. Even the fundamental types of protein aggregation appear to have some form of synergy with one another, with amyloid leading to tau aggregation, and the two being worse in combination than the individual contributions might lead one to expect. The only way to deal with Alzheimer's and other forms of late life dementia may be to fix it all: protein aggregation, inflammation, vascular dysfunction. This is actually a reasonable conclusion for any age-related disease when starting from the consideration of aging as damage accumulation and rejuvenation as damage repair.

Impact of the biological definition of Alzheimer's disease using amyloid, tau and neurodegeneration (ATN): what about the role of vascular changes, inflammation, Lewy body pathology?

The treatment of Alzheimer's disease (AD) is currently symptomatic and based on neurotransmitter manipulation, akin to what has been achieved in Parkinson's disease. Thus acetylcholine activity is being increased by cholinesterase inhibitors, and glutamatergic activity is being dampened by memantine action on NMDA receptors. A modest but clinically detectable response is present in many patients using such drugs alone or in combination. Unfortunately the next generation of drugs acting on AD core pathological factors such as amyloid deposition and phosphorylated tau aggregation has failed so far to delay disease progression, raising the issue of timing of these interventions along the continuum of AD neurodegeneration over time. This review wants to highlight the facts that other pathological factors are at play in AD, and deserve consideration in the full diagnostic assessment of the patients, and for treatment. These factors are vascular changes, Lewy body pathology, and neuroinflammation.

The clinical progression of AD is linked to specific neuropathological features, such as extracellular deposition of Aβ plaques, intracellular inclusions of tau protein in neurofibrillary tangles, and neuronal degeneration. Given that the presence of AD pathophysiology has been found across a broad clinical spectrum including individuals asymptomatic and with mild cognitive symptoms, biomarkers now play an important role in characterizing the trajectory of AD pathophysiology and have been incorporated in the AD diagnostic research criteria. These diagnostic research criteria recognize that the coexistence of abnormal Aβ and tau biomarkers better identify the preclinical and mild cognitive impairment (MCI) individuals who will progress to dementia over relatively short time frames of three to 5 years.

Based on histopathological and genetic evidences, fibrillar Aβ, the main constituent of Aβ plaques, has been postulated as the major driving force leading to AD dementia (Aβ cascade hypothesis). According to this hypothesis, all the resulting pathological processes are due to an imbalance between Aβ production and clearance, which would then potentiate the spread of tauopathy, leading to neurodegeneration and cognitive decline. However, the lack of consistent association between Aβ and clinical progression, and the fact that amyloid pathology has been found in cognitively normal elderly individuals challenge the Aβ hypothesis in its original form.

There is growing evidence that AD often coexists with cerebrovascular disease (CVD). They share many risk factors, leading to additive or synergistic effects on cognitive decline. Most AD patients have structural changes in their cerebral blood vessels. Imaging and pathological studies have demonstrated a high prevalence of arteriolosclerotic small vessel disease (SVD) in AD patients. Post-mortem and imaging studies demonstrate that arteriolar Aβ amyloid angiopathy, a sub-type of SVD, is more common in patients with AD than in elderly controls. The links between vascular factors and AD have been clearly confirmed both clinically and pathologically. However, there is a lack of high-quality therapeutic research to examine the extent to which vascular risk changes alter the course of AD. Further longitudinal mechanisms and therapeutic studies are needed, especially to determine whether the treatment of vascular risk factors can prevent or delay the onset of AD.

Although the accumulation of amyloid protein in plaques and tau protein in neurofibrillary tangles constitutes the core pathological feature of AD, the presence of abnormal brain aggregates of a third proteinopathy has been shown to be very prevalent in moderate and severe AD. Cytoplasmic inclusions of α-synuclein intraneuronally in Lewy bodies have been reported in up to 50% of sporadic AD cases and up to 60% of familial AD cases. Postmortem observations focusing on the influence of Lewy bodies have shown inconsistent results. However, it is worth mention that a well-powered multicenter study with a high sample size has reported that the onset of symptoms and death in AD individuals with Lewy bodies occurs at younger ages as compared to those without Lewy bodies, and that AD individuals with Lewy bodies have higher chance to be APOE ε4 carriers than AD individuals without Lewy bodies.

There is a growing body of evidence supporting neuroinflammation as an important player in the pathogenesis of AD. Neuropathological studies have shown the presence of activated microglia and inflammation related mediators in AD brains. Genetic studies show that several genes that increase the risk of sporadic AD encode factors that regulate microglial clearance of misfolded proteins and inflammatory reaction. Epidemiological studies further suggest that non-steroidal anti-inflammatory drugs (NSAIDS) can defer or prevent the onset of AD. Preclinical and post-mortem studies have consistently found that activated microglia colocalises with Aβ plaque, suggesting a close intimate relationship between microglia activation, Aβ and neuroinflammation. Several mechanisms have been hypothesised, including ongoing formation of Aβ and positive feedback loops between inflammation and amyloid precursor protein (APP) processing which compromise the cessation of neuroinflammation. Continued exposure to Aβ, chemokines, cytokines, and inflammatory mediators leads to microglia being chronically activated at the Aβ plaque site, which further contribute to Aβ production and accumulation in a vicious cycle.

Juvenescence Invests in AgeX Therapeutics

Juvenescence appears to be hitting its stride in initial setup. It will, once further along in its plan, look much like many of the private equity funds that exist in the biotech space, with a portfolio of mutually supporting companies working on therapies for various aspects of aging. We know that at least some of the principals, such as Jim Mellon, are supportive of the SENS rejuvenation research agenda, but it remains to be seen whether or not that will turn out in practice to involve investment in the young companies that have arisen in the SENS community in the past few years. The Juvenescence principals want to be making 5-10 million series A round investments, but if one happens to be looking for focused SENS startups coming up to that point, the list at present is not a long one. So, inevitably, there will be investment in infrastructure biotechnologies or things like mTOR inhibitors and NAD+ upregulation - approaches that I think are probably not going to move the needle all that much. There is a certain urgency in venture matters: once you have raised funds you can't then sit around and wait for the perfect opportunity.

It is my hope that Juvenescence will follow through with their declared intent to do more than just graze the crop of aging-related companies as they emerge, and will actively engage with the research and entrepreneurial communities to cultivate new projects and new companies. If there is one thing that all parties involved do poorly at present, it is the various steps of the transition from lab to entrepreneur. Researchers don't reach out to capital or entrepreneurs, there are too few entrepreneurs in biotech as a whole, not many of whom understand aging and the potential for rejuvenation therapies, and most institutions capable of deploying capital sit around waiting for entrepreneurs to show up with the science already nicely packaged with a bow on top. It is a crisis of inaction, and one of the reasons why there is a yawning gulf between research in the laboratory and clinical development in companies.

It is at least the case that anyone who builds a fund to make A-round investments is reliant on much larger movements of capital into the market later, in order to fund the really expensive work of pushing therapies through the regulatory process, and ultimately to purchase the companies in order to provide a return to investors. This means that the Juvenescence principals can be counted on to continue to loudly promote their agenda, and in doing so attract more support and funding to the vital field of rejuvenation research. It is a useful alignment of interests, one that creates a positive feedback loop once it is underway. Capital attracts capital, and in this case that will benefit us all in the long run.

Juvenescence aims to tap longevity 'money fountain'

Juvenescence, a UK start-up developing anti-ageing therapies, has raised 50m in Series A financing, with another 100m funding round planned for later this year and an initial public offering in 2019. Juvenescence is building a team of 20 scientists and drug developers in London who will co-ordinate its investments. The biggest investment so far is 8.3m in Insilico Medicine, an artificial intelligence company in the US that applies "deep learning" technology to drug discovery and ageing research. On Monday Insilico itself announced a funding round of 5m to 10m led by WuXi AppTec of China.

Also on Monday, Juvenescence announced a 5m investment in AgeX of California, which is using stem cell technology to regenerate human tissues that are failing through age-related degenerative disease. The most exotic investment is LyGenesis, a spinout from the University of Pittsburgh, which aims to use the patient's own lymph nodes as a bioreactor to grow a replacement organ if the original is destroyed by disease or fails in old age. It is focusing first on liver regeneration for people with end-stage hepatic disease, and future targets include the thymus, pancreas, and kidney. Juvenescence has also signed commercialisation deals with the Buck Institute for Research on Aging in California and is in negotiation with other biomedical organisations.

AgeX Therapeutics Closes on 5 Million Strategic Investment From Juvenescence

AgeX Therapeutics, Inc., a subsidiary of BioTime, Inc., focused on prolonging healthspan through an understanding of the fundamental mechanisms of human aging, today announced that it has closed a 5 million equity financing, through the sale of two million AgeX common shares to Juvenescence Ltd. "This investment, combined with the 10.8 million we previously raised from investors, the recently-announced cash received of approximately 3.2 million from the sale of Ascendance Biotechnology, and our recently-announced 386,000 grant from the NIH, provide sufficient capital for the continued development of our programs into 2020."

AgeX Therapeutics, Inc. is a biotechnology company focused on the development of novel therapeutics for age-related degenerative disease. The company's mission is to apply the proprietary technology platform related to telomerase-mediated cell immortality and regenerative biology to address a broad range of diseases of aging. The products under development include two cell-based therapies derived from telomerase-positive pluripotent stem cells and two product candidates derived from the company's proprietary induced Tissue Regeneration (iTR) technology.

Greater Fitness and Blood Vessel Elasticity Correlates with Slower Cognitive Decline

The quality of the vasculature is an important determinant of the pace of aging in the brain. There are probably several distinct processes involved, all of which tend to correlate with one another as aging progresses. Firstly the brain is an energy-hungry organ, but the network of tiny capillaries in tissues becomes less dense with age. A consequently lower supply of nutrients to cells causes loss of function. The same result may also occur due to the age-related weakening of the muscles of the heart. Secondly, blood vessels lose their elasticity in later life, and this in turn causes a rise in blood pressure as feedback mechanisms run awry. Higher blood pressure causes damage to sensitive tissues in many organs through a variety of means, such as a greater rate of rupture or blockage of tiny blood vessels. The brain of an older individual is riddled with the minuscule scars left by these events, and that damage adds up.

Why do blood vessels grow stiff with age? A mix of underlying causes, not all of which are fully understood. Persistent cross-links that our biochemistry cannot break down glue together structural proteins of the extracellular matrix, altering the structural properties of tissue. Rising inflammation and signals from senescent cells contribute to both calcification of blood vessel walls and dysfunction in the smooth muscle cells responsible for contraction and dilation. The behavior of smooth muscle is more responsive to lifestyle circumstances than other factors; better diet, avoiding excess fat tissue, and greater fitness are thought to have an impact, either through reduced inflammation and or other mechanisms, whereas there isn't much that can be done about existing calcification or cross-linking given the tools to hand today.

Greater fitness and better lifestyle choices only slow the progression of aging to some degree - and only meaningfully impact a fraction of its mechanisms. But in an era of rapid progress in medical biotechnology, in which the research community is finally waking to the potential of treating aging and its causes, it makes sense to adopt lifestyle choices that reliably help long-term health, even if the outcome at the end of the day is just a few years gained. Those few years may make a sizable difference, between on the one hand living long enough and in good enough health to benefit from future technologies of rejuvenation, and on the other hand missing that boat.

Better Physical Fitness and Lower Aortic Stiffness Key to Slower Brain Ageing

The rate of decline in certain aspects of memory may be explained by a combination of overall physical fitness and the stiffness of the central arteries, researchers have found. "Exactly why this occurs is unclear, but research indicates that exercise and physical fitness are protective. A healthier, more elastic aorta is also theorised to protect cognitive function, by reducing the negative effects of excessive blood pressure on the brain."

One hundred and two people (73 females and 29 males), aged between 60 and 90 years, living independently in aged care communities, were recruited. Their fitness was assessed with the Six-Minute Walk test which involved participants walking back and forth between two markers placed 10 metres apart for six minutes. Only participants who completed the full six minutes were included in the analysis, which assessed the stiffness of their arteries and cognitive performance. The researchers found that (along with Body Mass Index and sex) the combination of fitness and aortic stiffness explained a third of the variation in performance in working memory in older people.

Interestingly, physical fitness did not seem to affect central arterial stiffness, however only current fitness was assessed - long term fitness may be a better predictor of central arterial stiffness, however this has yet to be investigated. "Unfortunately, there is currently no effective pharmacological intervention that has proven effective in the long term in staving off dementia. The results of this study indicate that remaining as physically fit as possible, and monitoring central arterial health, may well be an important, cost effective way to maintain our memory and other brain functions in older age."

Physical Fitness and Aortic Stiffness Explain the Reduced Cognitive Performance Associated with Increasing Age in Older People

Greater physical fitness is associated with reduced rates of cognitive decline in older people; however, the mechanisms by which this occurs are still unclear. One potential mechanism is aortic stiffness, with increased stiffness resulting in higher pulsatile pressures reaching the brain and possibly causing progressive micro-damage. There is limited evidence that those who regularly exercise may have lower aortic stiffness. Our objective is to investigate whether greater fitness and lower aortic stiffness predict better cognitive performance in older people and, if so, whether aortic stiffness mediates the relationship between fitness and cognition.

Residents of independent living facilities, aged 60-90, participated in the study (N = 102). Primary measures included a computerized cognitive assessment battery, pulse wave velocity analysis to measure aortic stiffness, and the Six-Minute Walk test to assess fitness. Based on hierarchical regression analyses, structural equation modelling was used to test the mediation hypothesis. Both fitness and aortic stiffness independently predicted Spatial Working Memory (SWM) performance, however no mediating relationship was found. Additionally, the derived structural equation model shows that, in conjunction with BMI and sex, fitness and aortic stiffness explain 33% of the overall variation in SWM, with age no longer directly predicting any variation.

Thus greater fitness and lower aortic stiffness both independently predict better SWM in older people. The strong effect of age on cognitive performance is totally mediated by fitness and aortic stiffness. This suggests that addressing both physical fitness and aortic stiffness may be important to reduce the rate of age associated cognitive decline.

Clearance of Senescent Cells as a Therapy for Age-Related Muscle Loss and Frailty

Today's open access review looks over the evidence for senescent cells to contribute to the age-related loss of muscle mass and strength, leading to sarcopenia and frailty. Regular readers will know that the research community has found many mechanisms that are arguably important contribution to the characteristic weakness of old age. This part of the field is rife with competing evidence for processes ranging from the comparatively mundane, such as an inadequate dietary intake of protein in older people, to the highly complex, such as the biochemical disarray that causes loss of neuromuscular junctions, and the interactions between those junctions and mechanisms of muscle tissue maintenance. The most compelling evidence points to stem cell dysfunction as the primary cause of loss of muscle and strength with age. But then we might well ask which of the fundamental causes of aging produces that stem cell dysfunction?

The review here argues for cellular senescence to be an important cause. Senescent cells accumulate over time, a tiny fraction of the countless cells that become senescent every day managing to linger rather than self-destruct. The immune system clears out near all of those, but the immune system falters with age. Cancer is an age-related disease in large part because of this loss of capability in the portions of the immune system responsible for destroying errant cells, and the accumulation of senescent cells is no doubt in the same boat. Yet even in very old tissues, only a small percentage of cells are senescent. The harm they cause is not direct, but rather results from the potent mix of signals that they generate. Those signals produce chronic inflammation, destructively remodel tissue structure, and change the behavior of surrounding cells for the worse.

Just looking at chronic inflammation, it is known that this state can disrupt the normal processes of tissue maintenance and regeneration. But there are many other mechanisms worth surveying when it comes to the ways in which cellular senescence might be acting to suppress the activity of stem cell populations, thus leading to atrophy and loss of function in tissues such as skeletal muscle. What if these senescent cells could be removed, however? Might we expect some degree of rejuvenation of stem cell activity? That doesn't seem an unreasonable goal, based on the evidence to date. Senolytic therapies capable of clearing a fraction of senescent cells already exist, albeit not packaged up for the mass market, and not yet run through rigorous human trials. More effective therapies are entering the regulatory pipeline, under development in a number of young companies, and will arrive in the clinic over the years ahead.

Musculoskeletal senescence: a moving target ready to be eliminated

Aged individuals can deteriorate exceptionally fast after the onset of complications affecting the musculoskeletal system. Tissue erosion due to life-long mechanical and biological stress can ultimately result in pathologies such as osteoporosis, sarcopenia, and osteoarthritis, and contribute to frailty. While not all elderly people develop the same age-related diseases, virtually everyone will experience musculoskeletal complications sooner or later. To extend, and possibly even restore, healthy life expectancy in old age, it is essential to understand the cellular changes underlying musculoskeletal decline.

Tissue regeneration by stem-cell differentiation is critical in overcoming the relentless day-by-day damage to the musculoskeletal system. In young tissues, differentiation proceeds without much hindrance unless one exercises excessively or suffers undue levels of stress. However, during aging, the number and function of adult stem cells declines. For example, Pax7-expressing satellite stem cells, can replace damaged muscle fibers. Removing Pax7-positive cells from mice impairs muscle regeneration after injury, whereas increased availability of these cells enhances muscle repair.

In addition to cell-intrinsic regulation, muscle stem cell regenerative capacity also depends intimately on the microenvironment. During aging, the levels of inflammation chronically increase, an affect known as inflammaging. Evidence for this is provided by studies showing that muscle stem cells (satellite cells) from aged mice become more fibrogenic, a conversion mediated by factors from the aged systemic environment. In contrast, frailty is reduced by the JAK/STAT inhibitor Ruxolitinib, which reduces inflammation in naturally aged mice. Stem-cell impairing cues do not necessarily have to come from local sources but can travel over a distance. Therefore, there is a great interest in developing methods to interfere with the age-associated pro-inflammatory signaling profile. The question is how? To address this question, cellular senescence has recently gained attention as a potential candidate for intervention.

As we age, each cell in our body accumulates damage. Earlier in life, this damage is usually faithfully repaired, but over time more and more damage gets left behind. This can trigger a molecular chain of events, resulting in the entry of cells into a permanent state of cell-cycle arrest, called cellular senescence. Senescence can be invoked in healthy cells that experience a chronic damage response, either involving direct DNA damage or events that mimic the molecular response, such as telomere shortening or oncogenic mutations. As a consequence, these cells undergo an irreversible cell cycle arrest, effectively limiting the damage. So far, so good, except that senescent cells secrete a broad range of growth factors, pro-inflammatory proteins, and matrix proteinases that alter the microenvironment: the Senescence-Associated Secretory Phenotype (SASP).

Senescent cells persist for prolonged periods of time and eventually accumulate during aging. This also means there is a gradual and, importantly, ever-present build-up of deleterious molecules. Thus, senescence can have continuous detrimental effects on tissue homeostasis during aging. That senescent cells are a direct cause of aging was proven beyond a doubt in studies in which senescent cells were genetically or pharmacologically removed. In these studies, both rapidly and naturally aged mice maintained healthspan for much longer, or even showed signs of aging reversal.

Factors secreted by senescent cells can induce pluripotency in vivo. As such, these can impair normal stem cell function by forcing a constant state of reprogramming, something we dubbed a `senescence - stem lock'. Age-associated inflammation may thus deregulate normal stem cell function at different levels, for instance by preventing stem cells from producing differentiated daughter cells. Due to the constant secretion of SASP factors, senescent cells could thus impair local and distant stem cell function and differentiation in times of need. Here, we will highlight the interplay between senescence, the SASP and stemness in the individual musculoskeletal compartments: muscle, bone, and cartilage.

Not Everyone Feels the Urgent Need for Therapies to Treat Aging, and this is a Sizable Divide in our Broader Community

One of the many important points made by the advocacy community for rejuvenation research is that participants in the mainstream of medical science and medical regulation are not imbued with a great enough sense of urgency. We are all dying, and yet with each passing year the regulatory process moves ever more slowly, rejects an ever greater number of prospective therapies, becomes ever more expensive. The number of new therapies reaching the clinic falls. Regulators continue to reject the idea that treating aging is an acceptable goal in medicine. We live in an age of revolutionary progress in the capabilities of biotechnology, and yet patients must accept that new medicines are rare, and that fifteen years might pass between lab and clinic. This is not an industry moved by any sense of urgency.

Naturally, those who do see the urgency and are frustrated by the present state of medical development reach for different options. Some of those options are bad: cherry-picking research; testing interventions without evidence; self-experimentation without data or consideration of risk; building an industry to deliver supplements and other products that don't perform as advertised. Some of those options are sound: responsible development and medical tourism that takes place outside regions with the most onerous regulation; self-experimentation within a framework that encourages an understanding of risk and supporting research; advocacy to change the regulatory system.

Self-experimentation is the only way to obtain early access to new classes of medical technology, those described in research, manufactured in the marketplace, but not yet run through the regulatory process. Many will never even enter the regulatory process. The only way to provoke the sort of development needed to produce good data is for a community of self-experimenters to report on their experiences, obtaining a critical mass sufficient to attract research interest and funding. This is essentially what happened over the past few decades for the practice of calorie restriction. It isn't a medical technology, but proceeded through the same path of early research, adoption by self-experimenters, growth of a community, and that community then influenced the research community to pay greater attention. As a result we now have far better human data on calorie restriction, showing that the early research was essentially correct and it is a useful practice that modestly slows many of the consequences of aging.

Most people who self-experiment wouldn't call it that - and probably justifiably so. They rely on hope and how they feel rather than solid data, and are too readily swayed by hype and cherry-picked or misrepresented research. Many of those who went further than their own health to organize business ventures, such as the many members of the anti-aging marketplace, have built an industry that does at least as much harm as good. We cannot let the bad drive out the good when it comes to the frustration with the lack of urgency in medical development that leads people to choose to strike out on their own. It is possible to achieve meaningful gains through ventures in medical tourism, through responsible development, through self-experimentation with data and publication. Where this does happen, however, it is frequently the case that the people involved have a foot in both camps.

Such is the case for the principal subject of the popular science article here. I can't condone most of the activities of the Life Extension Foundation; the heart is absolutely in the right place, but so very much of the implementation is at best a waste, and at worse actively harmful to progress. Supplements as marketed over these past four decades do nothing for longevity, do nothing for aging, and participants in this market have used their advertising megaphone to convince the world that anti-aging is a sham, a joke: pills and potions that do nothing. It is an industry built on self-evidently false claims. Yet the Life Extension Foundation uses the proceeds from that business to fund some degree of meaningful, useful research into aging and means to treat aging and age-related disease. They also clearly support better paths forward in medical science. It is my hope that working rejuvenation therapies and biomarkers of aging will drive out the fraud and the lies and the nonsense in the years ahead, but don't ask me to approve of the state of this market today.

Bill Faloon has pursued immortality for decades. Now he's got lots of company. What does science have to say?

At 63, Bill Faloon is old enough to remember when talk of life extension labeled you a kook or charlatan. In the late 1970s, he co-founded the Life Extension Foundation, a nonprofit promoting the notion that people don't need to die - and later started a business to sell them the supplements and lab tests to help make that dream real. Nowadays he also distributes a magazine to 300,000 people nationwide and invites speakers to monthly gatherings at the Church of Perpetual Life, billed as a science-based, nondenominational meeting place where supporters learn about the latest developments in the battle against aging. Their faith is in human technologies that might one day end involuntary death.

After an hour of mixing, we all head to the second-­floor nave and fill the pews for the evening's event. Several rows back sits a beer scientist. Next to me, two women in dresses and heels. At the front, an elderly gentleman with hearing aids. Tonight's speaker is Aubrey de Grey, a biomedical gerontologist and chief science officer of SENS Research Foundation, a Mountain View, California, outfit that studies regenerative medicines that might cure diseases associated with old age.

Today, it is easy to locate university-affiliated labs at places such as Harvard and Stanford investigating their own interventions in the process of growing old. Since the National Institutes of Health established its Institute on Aging division in 1974, scientists have dedicated more and more resources to the challenge. Over the past dozen years, the NIA's budget has doubled to more than 2 billion. Faloon predates them all. These days, the several ­hundred people who regularly attend events at the church are personal validation for Faloon, who thinks that anyone his age and younger, given the proper physiological tweaking, could live to a healthy age of 130. The hope is that, by then, new solutions will make death truly optional. Yet no amount of self-tinkering can assure him and his followers that day will ever come.

Across all these potential aging interventions, there is one common denominator, and that is their fallibility. The medical community doesn't know what slows or reverses the process in humans, let alone what might cause harm. For that reason, researchers caution against the kind of self-experimentation Faloon practices. "We're playing with a new treatment paradigm," the Mayo Clinic's James Kirkland says of their research. "I've been around long enough to know there are going to be unpredictable things that happen as we get into people."

Faloon believes he faces a bigger risk from waiting than from being his own guinea pig. "I'm afraid that with aging research, some of the people don't have a sufficient sense of urgency," he says. He continually incorporates different interventions into his life-extension regimen. He restricts his calories to some 1,200 a day, about half what the average man consumes. He also ingests more than 50 medications daily, including metformin and Life Extension's own concoctions of nutraceuticals. "Anything that might work, I am doing," he says. Because he's impatient for clinical trials to yield ­conclusive results, Faloon gives about 5 million a year in profits from the buyers club to underwrite medical research. So far, the data from two recent studies on NAD+ and rapamycin that he backed are unpublished. "If we don't accelerate all these different projects, I'm not going to make it," Faloon says.

Evolution of Varied Life Spans without Antagonistic Pleiotropy

A successful evolutionary theory of aging must explain how a mix of species with shorter and longer life spans can emerge from a common ancestor with a longer life span. Putting theories of programmed aging to one side for a moment, as in that case one only has to argue that a shorter life span is more optimal for the ecological niche in question, antagonistic pleiotropy is the most readily available explanation for shorter lifespans to arise from natural selection. The theory here is that evolution selects for mechanisms and systems that both (a) ensure reproductive success in early life and (b) damage health in later life. There are all too many examples of biological systems that work well in childhood and youth, but inevitably fail because they are not capable of comprehensive repair and therefore accumulate damage, or because they are otherwise limited in some important capacity, and that limit will eventually be reached.

Can the evolution of shorter life spans appear in models without employing the assumption of antagonistic pleiotropy, and without invoking programmed aging, however? The authors of this paper argue that it can, and arises as an inevitable consequence of the dispersion of a population over the landscape. Interestingly, the details of the explanation touch on some of the same group dynamics - such as resistance to population collapse due to resource contention - that at least one programmed aging theorist employs to argue that aging must be selected. This is far from the only line of thought to approach group selection, which is still very much out of favor, while not being group selection.

With only a few exceptions, organisms deteriorate as they age and consequently die, but large variation in longevity still exists among species. A comparative study of 107 bird species found that fatty acid characteristics of cellular membranes have a prominent causative role in the aging process: species with longer maximum lifespans have higher proportions of long and monounsaturated fatty acids in their membranes. The question then arises as to why high proportions of long and monounsaturated fatty acids have not evolved in all species, given that this would maximize their lifespan and should therefore be promoted by natural selection, as aging is clearly detrimental for the fitness of individual organisms. In other words, why has a variability of lifespans evolved among species?

Evolutionary theory is still based on the antagonistic pleiotropy hypothesis: high mortality rates promote rapid reproduction, and direct selection for rapid reproduction leads to indirect selection for shorter lifespan. While this hypothesis has sometimes been supported by data from wild populations of animals, other empirical studies have frequently called into question the claimed role of extrinsic mortality in promoting senescence and the evolution of short lifespan.

Maybe as a response to this incapacity of the antagonistic pleiotropy hypothesis to provide a general explanation for the evolution of lifespan variability, some theoretical models have appeared in the last years based on the idea of programmed aging, stating that organisms have a genetically fixed senescence rate that is favored by natural selection because senescence may be adaptive in certain circumstances. These models have the important limitation of dealing with group selection, as they assume that senescence benefits lineages by avoiding overpopulation and associated problems such as resource depletion and epidemics, and thus lack an evolutionary logic. In fact, no genes exist that promote aging.

Here we propose that the evolution of lifespan is based on the ecological process of dispersal and does not depend on extrinsic mortality nor assume any adaptive benefit of aging, thus avoiding the above-mentioned limitations of group selection. Dispersal has previously been proposed in a theoretical model as a determinant of aging assuming that shorter dispersal distances create more competition for resources and shorter lifespans are then favored under such conditions because it would be beneficial for the lineages, therefore carrying the problems of group selection and programmed aging. Here we first provide theoretical arguments by which a similar dependence of lifespan evolution on dispersal distance can be achieved with basic concepts of population dynamics without the need of assuming adaptive group benefits or a genetic aging clock.

Our model considers that limited dispersal can generate, through reduced gene flow, spatial segregation of individual organisms according to lifespan. Individuals from subpopulations with shorter lifespan could thus resist collapse in a growing population better than individuals from subpopulations with longer lifespan, hence reducing lifespan variability within species. As species that disperse less may form more homogeneous subpopulations regarding lifespan, this may lead to a greater capacity to maximize lifespan that generates viable subpopulations, therefore creating negative associations between dispersal capacity and lifespan across species.

Leukotriene Inhibition Reverses Tau Aggregation and Neuroinflammation in Mice

Tauopathies are conditions in which accumulation of tau into neurofibrillary tangles causes dysfunction and cell death in the brain. Alzheimer's disease is the best known of these neurodegenerative conditions. Researchers here demonstrate an approach to reducing both tau aggregation and inflammation in mice, based on inhibition of leukotrienes. Mouse models of neurodegenerative conditions based on protein aggregation are highly artificial, as these forms of aggregation do not naturally occur in that species. This can produce misleading results, or at least results that have to be carefully assessed in the full understanding of the biochemistry involved, and how it might differ from that of humans. That said, the approach here does use an established pharmaceutical compound, meaning that there is a comparatively short path towards validation of the mechanism in human patients.

Researchers have shown, for the first time in an animal model, that tau pathology - the second-most important lesion in the brain in patients with Alzheimer's disease - can be reversed by a drug. The researchers landed on their breakthrough after discovering that inflammatory molecules known as leukotrienes are deregulated in Alzheimer's disease and related dementias. In experiments in animals, they found that the leukotriene pathway plays an especially important role in the later stages of disease. "At the onset of dementia, leukotrienes attempt to protect nerve cells, but over the long term, they cause damage. Having discovered this, we wanted to know whether blocking leukotrienes could reverse the damage, whether we could do something to fix memory and learning impairments in mice having already abundant tau pathology."

To recapitulate the clinical situation of dementia in humans, in which patients are already symptomatic by the time they are diagnosed, researchers used specially engineered tau transgenic mice, which develop tau pathology - characterized by neurofibrillary tangles, disrupted synapses (the junctions between neurons that allow them to communicate with one another), and declines in memory and learning ability - as they age. When the animals were 12 months old, the equivalent of age 60 in humans, they were treated with zileuton, a drug that inhibits leukotriene formation by blocking the 5-lipoxygenase enzyme. After 16 weeks of treatment, animals were administered maze tests to assess their working memory and their spatial learning memory. Compared with untreated animals, tau mice that had received zileuton performed significantly better on the tests. Their superior performance suggested a successful reversal of memory deficiency.

To determine why this happened, the researchers first analyzed leukotriene levels. They found that treated tau mice experienced a 90-percent reduction in leukotrienes compared with untreated mice. In addition, levels of phosphorylated and insoluble tau, the form of the protein that is known to directly damage synapses, were 50 percent lower in treated animals. Microscopic examination revealed vast differences in synaptic integrity between the groups of mice. Whereas untreated animals had severe synaptic deterioration, the synapses of treated tau animals were indistinguishable from those of ordinary mice without the disease. "Inflammation was completely gone from tau mice treated with the drug. The therapy shut down inflammatory processes in the brain, allowing the tau damage to be reversed."

The LEAF Rejuvenation Roadmap

The Life Extension Advocacy Foundation (LEAF) volunteers have started to maintain a Rejuvenation Roadmap resource. This is intended to be a reference and visual summary of the state of progress in the various lines of research the LEAF staff consider relevant to the treatment of aging as a medical condition. We can always disagree on the details, such as the choice to use the Hallmarks of Aging rather than SENS as a categorization strategy, but I think that this sort of project is very helpful as our community grows. New arrivals benefit greatly from summaries and starting points. In the years ahead the present set of disagreements found in summaries of the field and strategic choices in research should be washed away by data from clinical trials - questions of what works and what doesn't will start to have firm answers.

One of the most commonly asked questions we receive is "How is progress going in aging research?" It is something we are asked so often that we decided to provide the community with a resource that will help them to keep track of progress directly. To that end, today we have launched our new curated database, the Rejuvenation Roadmap, which will be tracking the progress of the many therapies and projects in the rejuvenation biotechnology field. This database aims to give a quick visual summary of the status of each drug or therapy along with some additional information for people interested in learning more about them.

We believe that an informed community is an effective one, and this was one of our motivations for developing this new database. There are many resources for scientists, such as the superb databases of the Human Ageing Genomic Resources maintained by Dr. João Pedro de Magalhães, which are excellent for researchers. However, we noticed that there was no database that tracked the efforts of the many researchers and projects in the field, and while some people do maintain lists, they are often not public facing, easy to access, or user-friendly.

Obviously, this is very much a work in progress, and the current list of therapies is relatively small, but it does give an idea of how it will work, and it is not hard to see how this could grow into a comprehensive resource for the community. The database will continue to grow and be updated as time passes, giving a unique, up-to-date overview of where the science and progress currently is. We hope that you like what we are doing with The Rejuvenation Roadmap and that you will find it useful.

For Many People, a Sizable Fraction of Age-Related Hypertension is Self-Inflicted

Secondary aging is, more or less, that part of age-related decline that is driven by lifestyle choices and environmental factors. It adds to the primary aging caused by internal processes that we can presently do comparatively little to address. The mechanisms involved are similar and overlapping. Chronic inflammation, for example, will grow in later life even given an exemplary approach to personal health, and contributes to the progress of all of the common age-related diseases. That is primary aging. But let yourself become overweight and take up a smoking habit, and greater levels of chronic inflammation will result. That is secondary aging.

The publicity materials here help to make the case that for much of the population, a sizable fraction of age-related hypertension - increases in blood pressure - is driven by unhealthy lifestyle choices. These are the usual suspects: a poor diet, excess fat tissue, lack of exercise. While one can't defeat aging and its varied manifestations by living well, actively making things worse seems like a poor choice in an age of accelerating progress in biotechnology, with rejuvenation therapies somewhere on the horizon. Whether or not one lives an extra few years, or experiences an extra decade of comparatively good health, is no longer moot in the long run. Some people will live for long enough to benefit from the coming era of progressively improving rejuvenation therapies, and some people won't. It makes sense to employ the sensible, everyday health practices that cost little and adjust the odds in your favor.

The program noted here is essentially a form of calorie restriction and/or calorie management, packaged up and prettified. That approach tends to work for people who are overweight, and will improve most health metrics as weight is lost, particularly those associated with metabolic disease deriving from excess fat and too little exercise. If this group and others manage to find ways to sell a lower calorie diet to people who wouldn't otherwise choose to benefit, then more power to them. It is a pity that we live in a world in which it doesn't work to comprehensively demonstrate, again and again, over decades, that fewer calories are better. Adoption requires the packaging and prettifying.

Researchers have demonstrated that a program aimed at helping people modify lifestyle factors such as diet and exercise is as effective as medication at reducing blood pressure. Participants in the study saw their blood pressure drop 19 points, on average, after taking part in the program for just 14 days. Other studies have shown that a blood pressure reduction of this magnitude can cut a person's risk of heart disease or stroke in half. "By adapting selected lifestyle health principles, half of the people in our study achieved normal blood pressure within two weeks while avoiding the side effects and costs associated with blood pressure medications. The Newstart Lifestyle program works quickly, is inexpensive and uses a palatable diet that allows for moderate amounts of salt and healthy fats from nuts, olives, avocado and certain vegetable oils."

The reduction in blood pressure accomplished by the program was equivalent to what can be achieved using three half-dose standard medications for blood pressure. In addition, 93 percent of the participants were able to either reduce the dose (24 percent) or eliminate their blood pressure medications (69 percent). People participating in the Newstart Lifestyle program follow a vegan diet, walk outside daily, drink substantial quantities of water, get adequate daily sleep and participate in optional spiritual activities. The program's vegan diet consists of foods, such as legumes, whole grains, vegetables, fruits, nuts, seeds, olives, avocados, soymilk, almond milk and whole-grain breads.

For the study, the researchers evaluated data from 117 people with high blood pressure who had participated in the Newstart Lifestyle program for 14 days. At the end of the program, half of the participants achieved a systolic blood pressure below the recommended 120 mmHg. The program was effective at lowering blood pressure in varying types of individuals, including otherwise healthy men and women and people with diabetes or who were obese and those with high cholesterol levels. Next, the researchers plan to test the program in more people over a longer time period to better understand its long-term effects and biological basis.

A Reminder that Excess Visceral Fat is Harmful

This popular science article takes a high level look at the vast array of research data showing that excess visceral fat causes great harm to long term health. One of the more important mediating mechanisms is an increase in chronic inflammation, a state of dysfunction in the operation of the immune system that disrupts organ function and tissue maintenance, and accelerates the development of all of the common age-related diseases. There are numerous other connections between the pace of aging and the activities of visceral fat tissue, however. Becoming overweight is the path to a shorter life expectancy, greater incidence of age-related disease, and higher lifetime medical expenditures.

In general, if your waist measures 35 or more inches for women or 40 or more inches for men, chances are you're harboring a potentially dangerous amount of abdominal fat. Subcutaneous fat that lurks beneath the skin may be cosmetically challenging, but it is otherwise harmless. However, the deeper belly fat - the visceral fat that accumulates around abdominal organs - is metabolically active and has been strongly linked to a host of serious disease risks, including heart disease, cancer, and dementia. Weight loss through a wholesome diet and exercise - activities like walking and strength-training - is the only surefire way to get rid of it.

Unlike the cells in subcutaneous fat, visceral fat is essentially an endocrine organ that secretes hormones and a host of other chemicals linked to diseases that commonly afflict older adults. One such substance is called retinol-binding protein 4 (RBP4) that was found in a 16-year study of nurses to increase the risk of developing coronary heart disease. This hazard most likely results from the harmful effects of this protein on insulin resistance, the precursor to type 2 diabetes, and development of metabolic syndrome, a complex of cardiac risk factors.

The Million Women Study conducted in Britain demonstrated a direct link between the development of coronary heart disease and an increase in waist circumference over a 20-year period. Even when other coronary risk factors were taken into account, the chances of developing heart disease were doubled among the women with the largest waists. Every additional two inches in the women's waist size raised their risk by 10 percent.

Cancer risk is also raised by belly fat. The chances of getting colorectal cancer were nearly doubled among postmenopausal women who accumulate visceral fat, a Korean study found. A Dutch study published last year linked both total body fat and abdominal fat to a raised risk of breast cancer. When the women in the study lost weight - about 12 pounds on average - changes in biomarkers for breast cancer, like estrogen, leptinm and inflammatory proteins, indicated a reduction in breast cancer risk.

Perhaps most important with regard to the toll on individuals, families and the health care system is the link between abdominal obesity and risk of developing dementia decades later. A study of 6,583 individuals in Northern California who were followed for an average of 36 years found that those with the greatest amount of abdominal obesity in midlife were nearly three times more likely to develop dementia three decades later than those with the least abdominal fat.

Over all, according to findings among more than 350,000 European men and women published in The New England Journal of Medicine, having a large waist can nearly double one's risk of dying prematurely even if overall body weight is normal.

How α-Synuclein Aggregration Kills Neurons in Parkinson's Disease

Parkinson's disease is strongly linked to quality control of mitochondria in neurons. The condition is characterized by the loss of a vital population neurons responsible for generating the neurotransmitter dopamine, and it is this loss that produces the tremors and other motor dysfunction observed in patients. Parkinson's disease is also a proteopathy, however, in which α-synuclein clumps together to form solid deposits that harm brain cells. In the research noted here, scientists show that this α-synuclein aggregation kills neurons by damaging mitochondria and triggering mitochondrial mechanisms that produce the form of cell death called apoptosis. This might suggest a link to what is already known of the important portions of the biochemistry of Parkinson's disease; more active mitochondrial quality control might slow the harm done by α-synuclein by removing damaged mitochondria before they can trigger apoptosis.

Parkinson's disease isn't the only synucleinopathy in which α-synuclein aggregation harms the function of the brain. Synucleinopathies are not the only class of proteopathy in the brain: amyloids and tau also form aggregates that are involved in the development of neurodegenerative conditions such as Alzheimer's disease. Finding ways to safely and reliably remove the excess molecular waste that accumulates within and between brain cells is a very important topic in medical research. Controlling one form of waste should provide benefits to patients suffering any of several varieties of neurodegeneration, but since aging brains tend to exhibit the signs of all of these forms of protein aggregate, clearing out all of them is most likely necessary in order to prevent or cure the most common age-related neurodegenerative conditions.

For years, scientists have known that Parkinson's disease is associated with a build-up of alpha-synuclein protein inside brain cells. But how these protein clumps cause neurons to die was a mystery. Using a combination of detailed cellular and molecular approaches to compare healthy and clumped forms of alpha-synuclein, researchers have discovered how the protein clumps are toxic to neurons. They found that clumps of alpha-synuclein moved to and damaged key proteins on the surface of mitochondria - the energy powerhouses of cells - making them less efficient at producing energy. It also triggered a channel on the surface of mitochondria to open, causing them to swell and burst, leaking out chemicals that tell the cell to die.

These findings were replicated in human brain cells, generated from skin cells of patients with a mutation in the alpha-synuclein gene, which causes early-onset Parkinson's disease. By turning patient skin cells into stem cells, they could chemically guide them into become brain cells that could be studied in the lab. This cutting-edge technique provides a valuable insight into the earliest stages of neurodegeneration - something that brain scans and post-mortem analysis cannot capture. "Our findings give us huge insight into why protein clumping is so damaging in Parkinson's, and highlight the need to develop therapies against the toxic form of alpha-synuclein, not the healthy non-clumped form."

Early Signs of Neurological Damage Observed in Hypertensive Individuals

A fair amount of research on raised blood pressure, hypertension, and its risks has been published of late. Hypertension is a downstream consequence of loss of elasticity in blood vessels. That loss of elasticity arises from the molecular damage at the root of aging, and the resulting hypertension is one of the more noteworthy mediating mechanisms by which that low-level biochemical damage is translated into structural damage to organs. Hypertension causes pressure damage to sensitive tissues, increasing the rate at which small blood vessels rupture, killing the nearby cells. This is particularly important in the brain, where regenerative capacity is limited. Individually, each tiny area of damage has little effect, but taken as a whole it adds up over time to contribute to cognitive decline.

A new study indicates that patients with high blood pressure are at a higher risk of developing dementia. This research also shows (for the first time) that an MRI can be used to detect very early signatures of neurological damage in people with high blood pressure, before any symptoms of dementia occur. High blood pressure is a chronic condition that causes progressive organ damage. It is well known that the vast majority of cases of Alzheimer's disease and related dementia are not due to genetic predisposition but rather to chronic exposure to vascular risk factors. The clinical approach to treatment of dementia patients usually starts only after symptoms are clearly evident. However, it has becoming increasingly clear that when signs of brain damage are manifest, it may be too late to reverse the neurodegenerative process. Physicians still lack procedures for assessing progression markers that could reveal pre-symptomatic alterations and identify patients at risk of developing dementia.

This work was conducted on patients with no sign of structural damage and no diagnosis of dementia. All patients underwent clinical examination to determine their hypertensive status and the related target organ damage. Additionally, patients were subjected to an MRI scan to identify microstructural damage. To gain insights in the neurocognitive profile of patients a specific group of tests was administered. As primary outcome of the study the researchers aimed at finding any specific signature of brain changes in white matter microstructure of hypertensive patients, associated with an impairment of the related cognitive functions.

The result indicated that hypertensive patients showed significant alterations in three specific white matter fiber-tracts. Hypertensive patients also scored significantly worse in the cognitive domains ascribable to brain regions connected through those fiber-tracts, showing decreased performances in executive functions, processing speed, memory and related learning tasks. Overall, white matter fiber-tracking on MRIs showed an early signature of damage in hypertensive patients when otherwise undetectable by conventional neuroimaging. As these changes can be detected before patients show symptoms, these patients could be targeted with medication earlier to prevent further deterioration in brain function. These findings are also widely applicable to other forms of neurovascular disease, where early intervention could be of marked therapeutic benefit.

How Amyloid Disrupts Synaptic Plasticity in Alzheimer's Disease

The research community continues to make progress, slow but steady, in understanding the low-level biochemistry of neurodegenerative conditions. It is a very complex area of study. You might compare the research here, focused on amyloid, with results noted yesterday, focused on α-synuclein. The aging of the brain is accompanied by the aggregation of a number of altered proteins, producing solid deposits and a halo of surrounding changes in cell biochemistry that damage or kill brain cells. Beyond that summary, each is very different in mechanisms and outcome. Regardless, the end result is cognitive decline, a disruption of function in the brain. Control of protein aggregation is a major focus of the research community, but achieving any meaningful progress towards that goal has proven to been far more challenging than was hoped when these projects began in earnest.

The accumulation of amyloid peptides in the form of plaques in the brain is one of the primary indicators of Alzheimer's disease. While the harmful effects of amyloid peptide aggregates are well established, the mechanism through which they act on brain cells remains ill-defined. Researchers knew, for instance, that amyloid peptides disrupt synapses - the area of contact and chemical communication between neurons - but did not understand how they did so. Now, new findings have revealed the molecular mechanism that links amyloid aggregates and deficient synaptic function observed in animal models of Alzheimer's disease: peptide oligomers interact with a key enzyme in synaptic balance, thereby preventing its normal mobilization.

The molecule, called CamKII, usually orchestrates synaptic plasticity, an aspect of neuronal adaptability that enables neurons to reinforce their responses to the signals they exchange. Groups of neurons that code for an information to be memorized are connected by synapses, which are themselves under the control of mechanisms of synaptic plasticity. When the connection between two neurons must be reinforced in order to memorize information, for instance during intense stimulation, CamKII is activated and leads to a chain of reactions that strengthen the capacity to transmit messages between these neurons.

Synaptic plasticity is central to memory and learning. Amyloid peptides prevent CamKII from participating in this process of synaptic plasticity, and this blockage eventually leads to the disappearance of the synapse. This discovery could find an application in early phases of Alzheimer's disease when initial cognitive deficiencies are observed, which could be linked to this synaptic malfunction. The goal for researchers now is to continue studying amyloid aggregates, especially by trying to prevent their interaction with CamKII and the loss of synapses observed during the disease.

Healthy Aging is an Oxymoron

For various historical reasons, none of them justified, researchers seeking to intervene in the aging process have avoided talking about extending human life span. Until comparatively recently, and after a great deal of work on the part of advocates such as those of the Methuselah Foundation and SENS Research Foundation, the leaders of the research and funding communities actively suppressed efforts to discuss or work on the treatment of aging as medical condition. This environment gave rise to euphemisms such as "healthy aging" or "successful aging," and the goal of compression of morbidity: extend the period of health within the present human life span, but never, ever talk about trying to extend that life span. This has distorted the scientific endeavor, holding back efforts to develop meaningful rejuvenation therapies.

"Healthy aging" is a nonsense phrase. Aging is, by definition, the rise in mortality risk, the growth in systemic damage and failure of function. Aging is the opposite of health. Yet the phrase is well established and unlikely to go away any time soon, sadly. Any researcher or institution settling on the goal of healthy aging sets up for defeat before the work even starts. To pursue healthy aging is to accept aging rather than seek to defeat it. It is to aim at small modulations of the aging process, tiny adjustments here and there, rather than the sweeping change of rejuvenation. It is the assurance of failure, of missing the opportunity to change the world for the better.

Expressions such as "healthy aging" and "aging gracefully" signify that while the aging processes are making no exception for you, you're relatively healthy and/or the cosmetic signs of aging aren't as pronounced as they could be. This, of course, betrays the obvious reality that, in general, this kind of aging isn't the norm but rather a special case. If things were the other way around, you wouldn't find any articles stating the obvious fact that it's possible to age gracefully; rather, you'd find articles saying that disgraceful or unhealthy aging, however exceptionally, may happen too.

This choice of words is rather problematic, especially now that the dawn of rejuvenation is visible on the horizon. The terms "healthy aging" and "successful aging" really are sharp contradictions in terms. If you read the scientific literature on aging, most if not all papers giving general introductions to the phenomenon define it as a chronic process of damage accumulation or a progressive decline in health and functionality. If we try to replace these definitions in the two expressions above, the results are frankly hilarious: "a healthy chronic process of damage accumulation" and "a successful progressive decline in health and functionality". What's that even supposed to mean? Given that this progressive decline in health and functionality happens of its own accord and it invariably kills you, one would think that you really don't need to put any special effort in achieving it, and it appears to be "successful" enough without any need for external intervention.

It's of course good that healthy aging, as defined as a mitigated and relatively disease-free decay process, is actively promoted. However, this unfortunate terminological choice perpetuates the false dichotomy between aging and age-related disease; it reinforces the completely unsubstantiated belief that you can age biologically and yet retain your health. To put it bluntly, it's one of the reasons why you have people saying that when their grandfather died, at age 95, he was "perfectly healthy". If everything with him was in perfect working order, what did he die of, exactly? Some may think he just died of "old age", as if old age were a separate cause of death entirely, but that's not the case. Death by old age is just an expression to mean that he died of one of the many health issues that, in humans, generally manifest only after the seventh or eighth decade of life.

Just like the term "life extension" - albeit somewhat improper - has become a proxy for the application of regenerative medicine for the prevention of age-related diseases, so "healthy aging" and similar phrases have become synonymous with "being less sick than you could be", even though they really sound more like "getting sick in a healthy way". The only way to eradicate these misleading expressions is to successfully explain the true nature of aging to the public.

B Cells May Drive Harmful Inflammation Following Heart Damage

The heart is one of the least regenerative organs in mammals. Damage to heart tissue, such as that resulting from a heart attack, produces a harmful inflammatory response and the formation of scar tissue rather than regeneration. Scarring disrupts normal tissue function, whether in the heart or elsewhere. The research community would like to suppress the unhelpful inflammation and scarring following injury in all types of tissue, but this phenomenon is particular problematic in the heart. Here, researchers demonstrate that the source of this inflammation may be largely the activity of B cells.

In a heart attack, blood is cut off from an area of the heart that then often dies. If the person survives, the body tries to heal the dead muscle by forming scar tissue - but such tissue can further weaken the heart. Yet another wave of damage can occur when well-intentioned immune cells try to heal the injured heart but instead drive inflammation. Pirfenidone is approved to treat a lung condition called idiopathic pulmonary fibrosis, a scarring of the lungs that has no known cause. The drug also has been known for its heart-protective effects in a number of different animal models of heart attack. Researchers had assumed that pirfenidone's protective action in the heart paralleled the reason it helps in lung disease. In the lungs, the drug slows the formation of scar tissue.

"That this drug also protects the heart is not new. But in our studies, pirfenidone didn't physically reduce scar tissue in the heart. The scar tissue is still there, but somehow the heart works better than expected when exposed to this drug. It wasn't clear why. So we set out to reverse engineer the drug to pick apart how it may be working. Since scar tissue was still present, we suspected inflammation was the main culprit in poor heart function after a heart attack." Most immune studies of the heart have focused on other types of immune cells, including macrophages, T cell lymphocytes, neutrophils, and monocytes. But the researchers found no differences in the numbers of such immune cells in the injured hearts of mice that received pirfenidone versus those that didn't. When they serendipitously measured B cells, however, they were surprised to see a huge difference.

"Our results showing B cells driving heart inflammation was quite unexpected. We didn't know that B cells have a role in the type of heart damage we were studying until our data pushed us in that direction. We also found that there isn't just one type of B cell in the heart, but a whole family of different types that are closely related. And pirfenidone modulates these cells to have a protective effect on heart muscle after a heart attack." When the researchers removed these cells completely, not only was the heart not protected, the beneficial effect of the drug went away. So the B cells are not exclusively bad, according to the scientists. "The protective effects of pirfenidone hinge on the presence of B cells. The drug may be working on other cells as well, perhaps directly or perhaps through the B cells. We're continuing to investigate the details."


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