Thoughts on the Ending Age-Related Diseases Conference

I made the pilgrimage to storied Manhattan last week for the first conference organized by the Life Extension Advocacy Foundation (LEAF), titled Ending Age-Related Diseases. It was well organized, all in all a very professional effort. Congratulations are due to the volunteers who set it all up and kept everything moving smoothly. The attendees were a mix of researchers, entrepreneurs, advocates, interested members of the public, and investors of various stripes – a good mix, one that in the present excitable market environment provoked a great deal of useful networking.

The presentations were recorded and will start to appear online as the LEAF volunteers process them. You should make a point of taking a look when they turn up, particularly the view from the investor side of the house. Investors who are personally interested in the success of a field are very different beasts from the run of the mill individual who mechanically seeks returns. They usually have an interesting perspective on the real world challenges inherent in turning a promising technology into a therapy, and that was the case here. The Fight Aging! audience is perhaps more familiar with the science, and so may find considerations of the business side of the house novel and interesting.

While attending the conference, I had a chance to meet in person a sizable number of people who I have only talked to via email over the past decade or more. I apologize to the apparently equally sizable number of people I didn’t have the chance to talk to during the breaks between presentations. Keith Comito of LEAF announced that the organization will be making this a yearly event, so I will endeavor to do better next year. Hopefully at that time I will have more interesting things to say about progress towards rejuvenation therapies at Repair Biotechnologies, and the state of the industry as a whole.

As I see things, this sort of mix of participants is very much needed in order to keep progress underway in our rejuvenation research community. We need a regular stirring up of the everyday patient advocates, the entrepreneurs and employees who build therapies, the scientists who discover new opportunities, and the investors who fund those tasks. Communication and building bridges are hard tasks, and there is ever a tendency to form camps and forget how to travel between them. There is a vast chasm between academia and commercial medical development, and all too many promising foundations for therapy fall in and are never seen again.

Is this because scientists are not doing enough to reach out to entrepreneurs and investors? Is it because there are too few entrepreneurs? That the universities make it too hard to license technologies developed in academia, discouraging investment across the field? That investors and their funds are sitting around waiting to be handed opportunities in a nice, neat package, rather than doing more legwork? I’m inclined to put more blame on the investor community simply because they have the resources to do better and more interesting things. They could work more systematically when it comes to reaching back into the research community to pick up promising work and assemble companies to develop it. Doing so in a robust, organized way will help all parties.

While at the conference, I buttonholed a number of people to espouse what we shall call the Dasatinib Empire concept. At this point in time, I think there is more than sufficient evidence to consider that dasatinib and quercetin in combination is most likely a useful, cheap senolytic treatment – a legitimate rejuvenation therapy that partially clears out the senescent cells that cause age-related disease and dysfunction. A single dose is in the $100 to $200 range, less if one shops cleverly, and one treatment every few years is likely close to the optimal dosage. Human trials, such as that ongoing at Betterhumans, will prove the benefits over the next few years, but it looks very compelling even right now. Dasatinib has side-effects that are very well categorized thanks to the past fifteen years of studies as a cancer therapeutic, and they appear neither onerous nor life-threatening in the senolytic scenario of a single dose once every few years, rather than the sustained dosing of cancer treatment.

Given this, and that dasatinib is a generic pharmaceutical, out of patent protection, why can’t someone build a serious non-profit or for-profit effort to deliver dasatinib and quercetin at scale to the tens of millions of older people who would benefit significantly from it? An initiative could finalize the human data currently in progress, and then it would be as much a matter of delivering information as delivering pharmaceuticals: anyone can set forth and obtain dasatinib if they only know how to do it. Doing this at scale would probably entail driving a very large truck through the loophole of off-label use of a generic drug, working to help as many older people as possible, as rapidly as possible, and then weaponizing favorable public opinion to fend off the inevitable attention of the FDA. Indeed, this could be a path to change the regulatory landscape, to force regulators to accept the treatment of aging as a fait accompli. I’d say this is a better, more aggressive, more plausible way to do it than the slow approach of trying to change the FDA from within.

It is the case that FDA officials, as a rule, are strongly opposed to the prospect of widespread off-label use, meaning the physician-ordered use of a treatment for something other than the purposes the FDA has approved. They see their role as protecting the population, and off-label use, while completely legal, is viewed as an end-run around their shield. However, and as I have argued in the past, the FDA is too much of a barrier, too strongly opposed to any and all risk, too unwilling to grant patients any choice in their own lives. The cost of that barrier is higher than the benefit. Why should so many millions of people suffer when the evidence strongly suggests that their suffering could be alleviated to some degree at low cost and little risk? Shouldn’t it be their choice?

Manhattan is a wealthy enclave. There are any number of individuals resident in that small section of New York real estate with the wealth, connections, and acumen to make something like the Dasatinib Empire a reality, were they to turn their attention to it for the years it would require. At some point it will become obvious to even those who have not watched the development of our longevity science community that the benefits of early senolytics are large, the costs are low, and there is thus much that might be accomplished in the world by joining up these dots. So I’ll keep mentioning this to people. Sooner or later it will happen.

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Physical Activity Correlates with a Reduced Impact of Aging in Later Life

The open access study noted here is one of many to show that greater levels of physical activity correlate well with a reduced risk of age-related disease. It isn’t possibly to reliably live to extreme old age on the back of a good exercise program, but that physical activity does reliably improve the odds of experiencing better rather than worse health in later life. Even small benefits can be worth chasing when they cost little and are reliably obtained, so long as that pursuit doesn’t distract from far more important initiatives. Exercise is beneficial, but it is no substitute for the rejuvenation therapies presently under development.

Successful aging has been defined as not suffering from chronic diseases, having optimal social engagement and mental health, and a lack of physical disability. Numerous studies have found that physical activity decreases the risk of many chronic diseases and increases longevity. However, the association between physical activity and successful aging has shown heterogeneity across studies. Some studies have shown either a lack of or a weak independent association between physical activity and successful aging; however, other cohort studies as well as systematic reviews have shown that higher levels of physical activity was associated with aging successfully.

Therefore, in our cohort study of 1,584 adults aged 49+ years at baseline we aimed to investigate whether total physical activity is independently associated with successful aging, which was defined as not experiencing disability and chronic disease (coronary artery disease, stroke, diabetes, cancer), having good mental health and functional independence, and reporting optimal physical, respiratory, and cognitive function during 10 years of follow-up. Participants provided information on the performance of moderate or vigorous activities and walking exercise and this was used to determine total metabolic equivalents (METs) minutes of activity per week.

Of the cohort, 249 (15.7%) participants had aged successfully 10 years later. Older adults in the highest level of total physical activity (more than 5000 MET minutes/week; n = 71) compared to those in the lowest level of total physical activity (less than 1000 MET minutes/week; n = 934) had 2-fold greater odds of aging successfully than normal aging. Our finding of a positive association between physical activity levels and successful aging is in agreement with the existing literature showing that physical activity might be an important parameter in enabling people to age successfully. Moreover, a systematic review found that the effect sizes for the association of successful or healthy aging with high levels of physical activity ranged from 1.27 to 3.09, which is in line with our observed estimate.

Link: https://doi.org/10.1038/s41598-018-28526-3

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Physical Activity Correlates with a Reduced Impact of Aging in Later Life

The open access study noted here is one of many to show that greater levels of physical activity correlate well with a reduced risk of age-related disease. It isn’t possibly to reliably live to extreme old age on the back of a good exercise program, but that physical activity does reliably improve the odds of experiencing better rather than worse health in later life. Even small benefits can be worth chasing when they cost little and are reliably obtained, so long as that pursuit doesn’t distract from far more important initiatives. Exercise is beneficial, but it is no substitute for the rejuvenation therapies presently under development.

Successful aging has been defined as not suffering from chronic diseases, having optimal social engagement and mental health, and a lack of physical disability. Numerous studies have found that physical activity decreases the risk of many chronic diseases and increases longevity. However, the association between physical activity and successful aging has shown heterogeneity across studies. Some studies have shown either a lack of or a weak independent association between physical activity and successful aging; however, other cohort studies as well as systematic reviews have shown that higher levels of physical activity was associated with aging successfully.

Therefore, in our cohort study of 1,584 adults aged 49+ years at baseline we aimed to investigate whether total physical activity is independently associated with successful aging, which was defined as not experiencing disability and chronic disease (coronary artery disease, stroke, diabetes, cancer), having good mental health and functional independence, and reporting optimal physical, respiratory, and cognitive function during 10 years of follow-up. Participants provided information on the performance of moderate or vigorous activities and walking exercise and this was used to determine total metabolic equivalents (METs) minutes of activity per week.

Of the cohort, 249 (15.7%) participants had aged successfully 10 years later. Older adults in the highest level of total physical activity (more than 5000 MET minutes/week; n = 71) compared to those in the lowest level of total physical activity (less than 1000 MET minutes/week; n = 934) had 2-fold greater odds of aging successfully than normal aging. Our finding of a positive association between physical activity levels and successful aging is in agreement with the existing literature showing that physical activity might be an important parameter in enabling people to age successfully. Moreover, a systematic review found that the effect sizes for the association of successful or healthy aging with high levels of physical activity ranged from 1.27 to 3.09, which is in line with our observed estimate.

Link: https://doi.org/10.1038/s41598-018-28526-3

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Physical Activity Correlates with a Reduced Impact of Aging in Later Life

The open access study noted here is one of many to show that greater levels of physical activity correlate well with a reduced risk of age-related disease. It isn’t possibly to reliably live to extreme old age on the back of a good exercise program, but that physical activity does reliably improve the odds of experiencing better rather than worse health in later life. Even small benefits can be worth chasing when they cost little and are reliably obtained, so long as that pursuit doesn’t distract from far more important initiatives. Exercise is beneficial, but it is no substitute for the rejuvenation therapies presently under development.

Successful aging has been defined as not suffering from chronic diseases, having optimal social engagement and mental health, and a lack of physical disability. Numerous studies have found that physical activity decreases the risk of many chronic diseases and increases longevity. However, the association between physical activity and successful aging has shown heterogeneity across studies. Some studies have shown either a lack of or a weak independent association between physical activity and successful aging; however, other cohort studies as well as systematic reviews have shown that higher levels of physical activity was associated with aging successfully.

Therefore, in our cohort study of 1,584 adults aged 49+ years at baseline we aimed to investigate whether total physical activity is independently associated with successful aging, which was defined as not experiencing disability and chronic disease (coronary artery disease, stroke, diabetes, cancer), having good mental health and functional independence, and reporting optimal physical, respiratory, and cognitive function during 10 years of follow-up. Participants provided information on the performance of moderate or vigorous activities and walking exercise and this was used to determine total metabolic equivalents (METs) minutes of activity per week.

Of the cohort, 249 (15.7%) participants had aged successfully 10 years later. Older adults in the highest level of total physical activity (more than 5000 MET minutes/week; n = 71) compared to those in the lowest level of total physical activity (less than 1000 MET minutes/week; n = 934) had 2-fold greater odds of aging successfully than normal aging. Our finding of a positive association between physical activity levels and successful aging is in agreement with the existing literature showing that physical activity might be an important parameter in enabling people to age successfully. Moreover, a systematic review found that the effect sizes for the association of successful or healthy aging with high levels of physical activity ranged from 1.27 to 3.09, which is in line with our observed estimate.

Link: https://doi.org/10.1038/s41598-018-28526-3

📍

Physical Activity Correlates with a Reduced Impact of Aging in Later Life

The open access study noted here is one of many to show that greater levels of physical activity correlate well with a reduced risk of age-related disease. It isn’t possibly to reliably live to extreme old age on the back of a good exercise program, but that physical activity does reliably improve the odds of experiencing better rather than worse health in later life. Even small benefits can be worth chasing when they cost little and are reliably obtained, so long as that pursuit doesn’t distract from far more important initiatives. Exercise is beneficial, but it is no substitute for the rejuvenation therapies presently under development.

Successful aging has been defined as not suffering from chronic diseases, having optimal social engagement and mental health, and a lack of physical disability. Numerous studies have found that physical activity decreases the risk of many chronic diseases and increases longevity. However, the association between physical activity and successful aging has shown heterogeneity across studies. Some studies have shown either a lack of or a weak independent association between physical activity and successful aging; however, other cohort studies as well as systematic reviews have shown that higher levels of physical activity was associated with aging successfully.

Therefore, in our cohort study of 1,584 adults aged 49+ years at baseline we aimed to investigate whether total physical activity is independently associated with successful aging, which was defined as not experiencing disability and chronic disease (coronary artery disease, stroke, diabetes, cancer), having good mental health and functional independence, and reporting optimal physical, respiratory, and cognitive function during 10 years of follow-up. Participants provided information on the performance of moderate or vigorous activities and walking exercise and this was used to determine total metabolic equivalents (METs) minutes of activity per week.

Of the cohort, 249 (15.7%) participants had aged successfully 10 years later. Older adults in the highest level of total physical activity (more than 5000 MET minutes/week; n = 71) compared to those in the lowest level of total physical activity (less than 1000 MET minutes/week; n = 934) had 2-fold greater odds of aging successfully than normal aging. Our finding of a positive association between physical activity levels and successful aging is in agreement with the existing literature showing that physical activity might be an important parameter in enabling people to age successfully. Moreover, a systematic review found that the effect sizes for the association of successful or healthy aging with high levels of physical activity ranged from 1.27 to 3.09, which is in line with our observed estimate.

Link: https://doi.org/10.1038/s41598-018-28526-3

📍

Physical Activity Correlates with a Reduced Impact of Aging in Later Life

The open access study noted here is one of many to show that greater levels of physical activity correlate well with a reduced risk of age-related disease. It isn’t possibly to reliably live to extreme old age on the back of a good exercise program, but that physical activity does reliably improve the odds of experiencing better rather than worse health in later life. Even small benefits can be worth chasing when they cost little and are reliably obtained, so long as that pursuit doesn’t distract from far more important initiatives. Exercise is beneficial, but it is no substitute for the rejuvenation therapies presently under development.

Successful aging has been defined as not suffering from chronic diseases, having optimal social engagement and mental health, and a lack of physical disability. Numerous studies have found that physical activity decreases the risk of many chronic diseases and increases longevity. However, the association between physical activity and successful aging has shown heterogeneity across studies. Some studies have shown either a lack of or a weak independent association between physical activity and successful aging; however, other cohort studies as well as systematic reviews have shown that higher levels of physical activity was associated with aging successfully.

Therefore, in our cohort study of 1,584 adults aged 49+ years at baseline we aimed to investigate whether total physical activity is independently associated with successful aging, which was defined as not experiencing disability and chronic disease (coronary artery disease, stroke, diabetes, cancer), having good mental health and functional independence, and reporting optimal physical, respiratory, and cognitive function during 10 years of follow-up. Participants provided information on the performance of moderate or vigorous activities and walking exercise and this was used to determine total metabolic equivalents (METs) minutes of activity per week.

Of the cohort, 249 (15.7%) participants had aged successfully 10 years later. Older adults in the highest level of total physical activity (more than 5000 MET minutes/week; n = 71) compared to those in the lowest level of total physical activity (less than 1000 MET minutes/week; n = 934) had 2-fold greater odds of aging successfully than normal aging. Our finding of a positive association between physical activity levels and successful aging is in agreement with the existing literature showing that physical activity might be an important parameter in enabling people to age successfully. Moreover, a systematic review found that the effect sizes for the association of successful or healthy aging with high levels of physical activity ranged from 1.27 to 3.09, which is in line with our observed estimate.

Link: https://doi.org/10.1038/s41598-018-28526-3

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An Interview with Peter de Keizer of Cleara Biotech

The Life Extension Advocacy Foundation volunteers recently published a long and interesting interview with Peter de Keizer, the researcher who led development of the FOXO4-p53 approach to selective destruction of senescent cells. As senescence cells cause aging and age-related disease, there is considerable interest in developing means to remove them, and thus produce rejuvenation. The FOXO4-DRI used in de Keizer’s study is probably the best of the current crop of senolytic compounds, as while the degree to which it kills senescent cells is broadly similar to the others, the evidence to date suggests that it produces insignificant side-effects; its method of action is much more localized to senescent cells. A company, Cleara Biotech, has been funded to develop this research into a commercial therapy.

It doesn’t seem like as many people in Europe talk about aging as in the U.S. Is being in Europe instead of the U.S. better or worse for your research?

As usual, the U.S. innovates, China imitates, and Europe hesitates. I returned to Europe for personal reasons, but I have been talking to American investors who want to explore Europe a bit more, and there are possibilities. People here do acknowledge aging as a problem, and the Undoing Aging conference in Berlin was a success. The downside with Silicon Valley is that there are big budgets and a great spirit, but we also need a style of research, which is, in every city, a little bit different. In Europe, the focus is very much molecular. I would like to combine the great vision and budget of Silicon Valley with European quality and maybe a bit of skepticism. We never publish anything unless we are really convinced. In that sense, I like Europe because people are interested in aging here; you just have to talk to the right people, and many people are skeptical. When I talk to scientists about what we do, they also get excited.

Are the regulations regarding trials more stringent than in the U.S.?

Yes, that’s true, especially for animal work. There’s a lot of societal pressure not to do animal work. We have to deal with these hurdles, but there’s good money in science here, certainly in Western Europe, and we can make do quite well. This is generalizing, but we tend to talk less and do more.

Would you say that a potential side effect of the drug, if not used at the proper dose, could be excessive lysis?

The honest answer is “We don’t know.” I’ve seen in mice that you can go too far; if you look at the cell data, it’s tenfold more potent against senescent cells. That sounds like a lot, but if you want to treat relatively healthy people with this, if one in ten cells that will be destroyed is basically a healthy cell, I find it very risky. So, you need to have a perfect dose or a perfect range.

With mice, we could scale it and we could say if it’s too much or not, but for humans, it’s more difficult. What we’re doing now is trying to optimize this to make it tenfold more selective. This is version 4, and the published paper is on version 3; the first two were generated in the US in 2012, and they were not so effective. The first step was very short and had a very poor solubility, the second step lasted much longer, and the third peptide we made in D-amino acid is the one we published now. Now, we’re making the fourth one because we know where the critical amino acids and the non-important and important ones are in the interaction domain of the two proteins, FOXO4 and p53. We plan on giving number 4 to a team of drug development experts to get it to a hundredfold selectivity, and then it should be much safer for use.

How long would you say it’s going to be for this safe version four to be optimal?

That’s the fun part. It took me ten years to come to this third version because in academia, we always have 20 other things that are also interesting. Now, we actually teamed up with a company, Cleara, that we founded just recently. The team has 20 people, with 10 structural experts, and they’re going crazy on this. Every week, we have a meeting at which they have made some more progress, and it is super fast. We gave ourselves four months for a library screen on the first version, and then it’s another ten rounds of optimizations. Once we have a lead candidate, we will start doing all the things that academia never wants to look at, like a liver update and all the stuff that scientists aren’t interested in but is important to have. I want to do ten rounds of that, and it’s three weeks per round, then we’ll know roughly where the weak spots are in our current version, and we can go back and add heavy metal toxicity, etc. We gave ourselves a year for optimization, but I hope sooner.

How well does this treatment compare to other treatment options, such as fasting?

With fasting, you don’t kill, you just delay the secretions from senescent cells. It’s like rapamycin and aspirin; it just blocks the secretion profile. Fasting offers a transient benefit for sure, but a week later, you eat again, and they’re just there again. It’s just making them dormant. We have not seen evidence that senescent cells are removed by fasting, in mice or in cells.

Have you looked at other senolytics?

We tried a lot, and the BCL inhibitors look the most promising. What we saw when comparing them to FOXO4-DRI is that they are toxic at low levels and should not be given to healthy people. That’s the downside of these drugs. In vitro, if you do low-level navitoclax on healthy cells, you get 10, 20 percent cell death. That’s relatively stable. That’s a decrease in viability because you’re affecting some cells that are apparently sensitive to BCL inhibition. We did not see that with FOXO4, and that’s what’s reported in our paper. As for quercetin and dasatinib, I’m absolutely not a fan of those. We’ve tried a couple of experiments; we’ve never seen a good result.

How often do you think people would need senolytic treatments, will they be for older or younger people?

In mice, over a year; we did it once a month. It seemed to be enough, and I think we can actually reduce that frequency. But, I still have to do the experiment. If we do it once in a while, once every three months, once every half a year in mice, it might actually be sufficient. I don’t think they accumulate that fast. Maybe later in life, you’ll do it a bit faster. Early in life, there’s really no reason to do it so often. It’s like a car. If it’s only a couple of years old, you don’t go to the mechanic as often.

Link: https://www.leafscience.org/dr-peter-de-keizer/

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Hematopoietic Cells are Impacted by Cellular Senescence in Old Humans

Hematopoietic stem and progenitor cell populations are responsible for generating immune cells. Their decline is one of the causes of immune failure with age, as the pace at which new immune cells are created falters. There are other equally important issues in immune aging, such as the atrophy of the thymus, where T cells of the adaptive immune system mature, and the accumulation of malfunctioning immune cells in older individuals, but we’ll put those to one side for this discussion.

Stem cell decline with aging is a complicated business with many contributing causes, and the relative importance of those causes seems to differ between populations and tissues. Few stem cell populations are very well studied when it comes to asking why exactly it is that they decline in activity with age. Those that are, such as muscle, hematopoietic, and neural populations all seem to be quite different. Muscle stem cells decline in activity but, given the right signals, appear quite ready to go back to work with minimal signs that they are greatly impacted by damage. Hematopoietic stem cells do appear to be more damage-limited, however.

In this open access paper, the authors look at the detrimental impact of cellular senescence on hematopoietic cells, and thus on the immune cells that they produce. Cellular senescence is a reaction to damage or excessive replication; senescent cells cease to replicate, and most such cells self-destruct or are destroyed by the immune system. Some linger, however, and the harmful, inflammatory mix of signals that they generate are implicated as a cause of degenerative aging. Studies in mice show that removing senescent cells improves health and extends life span. There are also populations of cells that show some of the markers and behaviors of senescence, but have yet to be definitively classified as senescent – nothing is simple when it comes to cellular biology. This pseudo-senescence or maybe-senesence may be the case here; more research will determine whether or not this is the case.

Elderly human hematopoietic progenitor cells express cellular senescence markers and are more susceptible to pyroptosis

Aging is associated with an increased prevalence of multiple comorbidities, including infectious and malignant diseases. Many of these disorders are thought to stem from old-age-related immune decline. Increasing efforts to characterize the immune system of elderly people in recent years have revealed that most immunocompetent cell compartments present profound quantitative as well as qualitative impairments. The cause of these impairments can vary, and is often related to the exhaustion of the cells or their functions over time in inflammatory settings.

The majority of mature blood cell compartments need, therefore, to be continuously replenished or replaced, which is the role of hematopoietic progenitor cells (HPCs) and, ultimately, hematopoietic stem cells (HSCs). While the self-renewal and differentiation potential of stem cells, along with their blood cell reconstitution capacity, have long been considered as infinite, increasing evidence indicates that this is not the case. Under conditions of stress, HSCs eventually exhibit several functional defects, including a diminished regenerative and self-renewal potential. Loss of stem cell activity is therefore a likely mechanism of impairment common to many mature cell types, thus representing a central cause of immune-competence decline.

Most studies on HSC aging have been carried out in mouse models, and have highlighted extrinsic and intrinsic factors affecting the function of HSCs. A recent study reveals that loss of autophagy in most HSCs from aged mice causes an activated metabolic state, which is associated with accelerated myeloid differentiation, and impairs HSC self-renewal activity and regenerative potential. In humans, much less information is available on the aged HSCs, due to the limited and challenging access to bone marrow samples of elderly humans, the niche of HSCs. Reduced transplantation success in patients receiving HSCs isolated from older (45 years and above) donor bone marrows indicates that human HSC regenerative capacity also declines with aging.

We performed here a comprehensive study of blood HPCs, as an alternative to bone marrow HSCs, to overcome the constraint of sample availability from elderly adults. Based on phenotypic analyses, in vitro T lymphocyte differentiation assays, and gene expression profiling of circulating HPCs from aged subjects, we demonstrate impaired lymphopoiesis and active cell cycling of HPCs with aging, and provide insights into their functional impairments. Our findings reveal that, while mobilized, elderly HPCs present evidence of cellular senescence and increased cell death by pyroptosis. Reduced telomere length and telomerase activity in old HPCs may affect the properties of their progeny, such as mature T lymphocytes. This pre-senescent profile is characteristic of the multiple intrinsic and extrinsic factors affecting HPCs in elderly individuals and represents a major obstacle in terms of immune reconstitution and efficacy with advanced age.

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Reviewing Waste Clearance in the Brain via the Glymphatic System

Clearance of metabolic waste from the brain via fluid drainage pathways is becoming an important topic in the context of age-related neurodegeneration, as is noted by the authors of this open access review paper. There is good evidence to suggest that drainage of cerebrospinal fluid is a significant path for the removal of wastes, such as the protein aggregates associated with dementia, and that the relevant fluid channels atrophy and fail with age. That decline may well be an important contribution to the development of neurodegenerative disease in later life, and the first efforts to do something about it are now underway. Restoring drainage is the goal of Leucadia Therapeutics, for example, a company that will probably be joined by similar initiatives in the years ahead.

Waste removal from the central nervous system is essential for maintaining brain homeostasis across the lifespan. Two interconnected, dynamic networks were recently uncovered, which may provide new information concerning the conundrum of how the brain manages waste removal in the absence of authentic lymphatic vessels (LVs). The glymphatic system serves as the brain’s “front end” waste drainage pathway that includes a perivascular network for cerebrospinal fluid (CSF) transport, which is connected to a downstream authentic lymphatic network associated with the meninges, cranial nerves, and large vessels exiting the skull. The anatomical and functional components of the two systems are complex, and the processes by which they physically interconnect are only partly understood.

The first pioneering studies documented that soluble amyloid beta (Aβ) protein and tau oligomers – metabolic waste products whose buildup is associated with Alzheimer’s disease (AD) – were transported from the interstitial fluid (ISF) space and out of the brain via the glymphatic system. This information was followed by another hallmark study reporting that slow wave sleep enhanced glymphatic Aβ clearance from brain when compared to wakefulness. Collectively, this information was met with excitement in the neuroscience and clinical communities because maintaining efficient brain waste drainage across the lifespan – possibly by preserving normal sleep architecture – emerged as a novel therapeutic target for preventing cognitive dysfunction and decline.

The idea of maximizing brain “waste drainage” as a new preventive or therapeutic target for neurodegenerative disease states was further strengthened by animal studies providing evidence of declining glymphatic transport efficiency in healthy aging, AD models, traumatic brain injury, cerebral hemorrhage, and stroke. Considering the novelty of the glymphatic system concept, along with the rapidly emerging literature associating key physiological processes (e.g., vascular pulsatility, and sleep) with glymphatic transport function and waste solute outflow from brain, we decided it was timely to review this information cohesively. Hence, the goal of this mini-review is to provide a broad overview of the current data, controversies, and gaps in knowledge of the glymphatic system and waste drainage from the brain, while addressing potential consequences of aging as well as critically reviewing evidence for its existence in the human brain.

Link: https://doi.org/10.1159/000490349

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Vinculin Upregulation Improves Cardiovascular Health and Extends Life in Flies

Researchers here report on a single gene alteration in fruit flies, increased levels of vinculin, that improves cardiovascular function in later life and increases life span. Effect sizes in flies are much larger than those in humans, where is is possible to directly compare interventions. Short-lived species have evolved to exhibit a far greater plasticity of longevity in response to environmental and genetic changes, at least in those methodologies tested to date. It remains to be seen as to whether the initial hypothesis on the important mechanisms linking vinculin levels to improved health turn out to be correct. Vinculin is involved in common cellular processes that in turn influence many aspects of tissue function. This is frequently the case in studies of slowed aging – finding out exactly how and why it works is a long and arduous process.

Our cells tend to lose their shape as we grow older, contributing to many of the effects we experience as aging. This poses particular problems for the heart, where aging can disrupt the protein network within muscle cells that move blood around the body. Researchers discovered that maintaining high levels of the protein vinculin – which sticks heart muscle cells to one another – confers health benefits to fruit flies. Their work shows that fruit flies bred to produce 50 percent more vinculin enjoyed better cardiovascular health and lived a third of their average life span longer.

Vinculin works at the intercalated disks that glue together heart muscle cells, called cardiomyocytes. As we age, cardiomyocytes make less vinculin. Vinculin organizes the heart’s contractile proteins, so as vinculin levels fall our heartbeats become disorganized and less efficient. By breeding flies with complementary genes, researchers created a genetic switch that turned on extra copies of the vinculin-coding gene. To ensure that only cardiomyocytes were producing the protein, the group used the same activation machinery as a heart development gene called Tinman.

While typical fruit flies live for roughly six weeks, flies that made more vinculin survived up to nine weeks. Additionally, flies with a vinculin boost were more active and able to climb the walls of their enclosures, a test of fruit fly athletic ability. Researchers were surprised how much improving cardiac function also helped the flies maintain a healthier metabolism. To measure this improvement, researchers fed the flies a special form of glucose and detected how the flies modified and used the sugar. Flies with more vinculin broke down more glucose than their counterparts. The team concluded higher vinculin levels in the flies’ hearts enabled other organs to efficiently get the nutrients they needed in the breakdown process.

Link: https://publishing.aip.org/publishing/journal-highlights/high-vinculin-levels-help-keep-aging-fruit-fly-hearts-young

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