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- A Mechanism by which Autoimmunity Raises the Risk of Cardiovascular Disease
- More Evidence for the Genetic Contribution to Longevity to be Smaller than Suspected
- Senolytic Therapeutics Uses Nanotube-Carried Toxins to Destroy Senescent Cells
- Jim Mellon Donates 100,000 to the SENS Research Foundation Year End Fundraiser
- The Milken Institute's Longevity Innovators Interviews
- Even Mild Hypertension is Harmful to Health
- Extracellular NAD+ Declines with Age
- A Popular Science View of Checkpoint Inhibitor Cancer Immunotherapies
- Does the Altered Blood Flow of Atrial Fibrillation Contribute to Dementia?
- Klotho Shields the Brain from the Peripheral Immune System, but Declines with Age
- mTORC1 at the Intersection of Aging and Type 2 Diabetes
- Growing Enthusiasm for the Development of Geroprotectors
- Antihypertensive Use Correlates with Higher Epigenetic Age Despite Reduced Mortality
- Initial Evidence for the Antibiotics Azithromycin and Roxithromycin to be Senolytic
- USP13 Inhibition Clears Lewy Bodies in a Mouse Model of Parkinson's Disease
A Mechanism by which Autoimmunity Raises the Risk of Cardiovascular Disease
In autoimmunity, the immune system becomes dysregulated and mistakenly attacks portions of the patient's own biochemistry. The broad variety of autoimmune conditions are differentiated from one another on the basis of exactly which structures and cells come under attack. Some autoimmune conditions are highly disabling or lethal, while others are comparative mild, but even lesser autoimmune conditions such as rheumatoid arthritis still shorten life expectancy. To the degree to which autoimmunity results in increased inflammation, a shorter life is the expected outcome, even when the tissues targeted by the immune system are less vital. Chronic inflammation is a major downstream mechanism of aging, and speeds the development and progression of all of the common fatal age-related conditions.
Most autoimmune disorders are comparatively poorly understood. The immune system is enormously complex, and far from completely mapped. Many of the autoimmune conditions in which etiology remains obscure may turn out to be collections of distinct conditions with varied causes and a similar outcome. Further, numerous forms of autoimmunity tend to arise with age as the immune system becomes worn and dysfunctional, and are presently lumped in with the other serious consequences of a failing immune system. These age-related autoimmunities are even less well understood than their more widely recognized counterparts, and it is very likely that many more remain to be discovered in the first place, let alone comprehensively investigated. Consider that the prevalent late life condition of type 4 diabetes was only cataloged a few years ago, for example.
Why does autoimmunity shorten life spans? Cardiovascular disease is the obvious candidate, and inflammation is the obvious link to investigate wherever there is a raised risk of cardiovascular mortality. Researchers here narrow down the connection to the inflammatory cytokine interleukin-17, and show that it is possible prevent the increased cardiovascular disease risk by blocking interleukin-17, at least in mice. This in turn suggests that existing drugs targeting this cytokine, used to treat some autoimmune conditions, might reduce cardiovascular disease risk in older people without autoimmunity. This is one of many examples to suggest that sophisticated control over inflammation could slow the progression of aging to some degree.
Link between autoimmune, heart disease explained in mice
People with psoriasis and lupus are two to eight times more likely to suffer a heart attack than people without these diseases. For young and middle-aged adults with rheumatoid arthritis, cardiovascular disease is the top cause of death. Psoriasis is characterized by patches of red, thickened, scaly skin. The thickening is partly due to an excess of collagen, the main protein in connective tissues such as skin and blood vessel. Researchers suspected that the walls of blood vessels also might be webbed with too much collagen. They created a light-sensitive form of high-density lipoprotein (HDL) - the molecular carrying case for cholesterol - that fluoresces when hit with a laser beam, and inserted it into mice. The researchers then induced a psoriasis-like disease in the mice.
By following the fluorescent cholesterol carrier, the researchers could see that HDL cholesterol was delayed in getting out of the bloodstream in the mice that received the compound. This was true not only in the skin, but in internal arteries near the heart. In addition, the skin and blood vessels were more densely interlaced with collagen and more resistant to stretching. Further, when the researchers fed mice a high-cholesterol diet for three weeks, the mice in the experimental psoriasis group developed significantly larger cholesterol deposits in their blood vessels.
An immune cell type called Th17 cells multiplies robustly in autoimmune diseases such as psoriasis, lupus, and rheumatoid arthritis, releasing copious amounts of the immune molecule IL-17. When the researchers neutralized IL-17 in mice with psoriasis-like disease, using an antibody, collagen density went down and cholesterol deposits shrank. "It'll take a few years before we know for sure, but we predict that the anti-IL-17 antibodies that already are being used to treat autoimmune diseases will be effective at reducing risk of cardiovascular disease."
Interleukin-17 Drives Interstitial Entrapment of Tissue Lipoproteins in Experimental Psoriasis
Lipoproteins trapped in arteries drive atherosclerosis. Extravascular low-density lipoprotein undergoes receptor uptake, whereas high-density lipoprotein (HDL) interacts with cells to acquire cholesterol and then recirculates to plasma. We developed photoactivatable apoA-I to understand how HDL passage through tissue is regulated. We focused on skin and arteries of healthy mice versus those with psoriasis, which carries cardiovascular risk in man. Our findings suggest that psoriasis-affected skin lesions program interleukin-17-producing T cells in draining lymph nodes to home to distal skin and later to arteries. There, these cells mediate thickening of the collagenous matrix, such that larger molecules including lipoproteins become entrapped. HDL transit was rescued by depleting CD4+ T cells, neutralizing interleukin-17, or inhibiting lysyl oxidase that crosslinks collagen. Experimental psoriasis also increased vascular stiffness and atherosclerosis via this common pathway. Thus, interleukin-17 can reduce lipoprotein trafficking and increase vascular stiffness by, at least in part, remodeling collagen.
More Evidence for the Genetic Contribution to Longevity to be Smaller than Suspected
How much of the natural human variation in longevity and pace of aging has its roots in genetics, and how much is determined by lifestyle and environment? Some gene variants result in beneficial metabolic alterations such as lower cholesterol or a greater resilience in the face of the molecular damage of late old age. Lifestyle choices such as calorie intake and exercise clearly influence long term health and mortality. Similarly, exposure to pathogens and pollutants can accelerate the pace of aging via their interaction with the immune system. The consensus of the past few decades had come to be that the split is around 25% due to gene variants versus 75% due to choice and environmental factors.
Large vaults of familial history data have been created since the advent of the internet, one of the many consequences of ubiquitous, low-cost channels of communication. Data of all varieties is more easily collected, stored, and analyzed. More rigorous analysis of this historical data of human lineages is now suggesting that the genetic contribution to longevity is much smaller than thought. The study here can be compared with a similar effort published last month. That both came to roughly the same conclusions, via quite different methods of analysis, is worth bearing in mind when balancing this against earlier, higher estimates of the degree to which genes determine life expectancy.
Our goal for the next few decades is, of course, to make all of this analysis a quaint curio that is only of interest only as part of a vanished past - a consideration of how the human system worked in the absence of rejuvenation therapies, to be placed next to work on the spread of smallpox and tuberculosis through populations lacking any effective treatment. When aging can be controlled through medical technology, and when those therapies are universally available, there will be only academic interest in how aging functions in people who have no access to rejuvenation therapies. Even the first, crude rejuvenation therapies that are now available, the pharmaceutical senolytics that selectively destroy a fraction of senescent cells in old tissues, will have a greater effect on human life span than near all genetic variants found in the wild.
Family tree of 400 million people shows genetics has limited influence on longevity
Calico Life Sciences and Ancestry teamed up to use publicly available pedigree data to approach the problem of figuring out the genetic contributions to human longevity. The heritability of life span has been well investigated in the literature, with previous estimates ranging around 15-30%. But some of these studies found that it wasn't just blood relatives who shared similar life spans - so did spouses. This suggested that the heritability estimates might have been confounded by shared environments or assortative mating (the tendency to choose mates who have similar traits to ourselves). Starting from 54 million subscriber-generated public family trees representing six billion ancestors, Ancestry removed redundant entries and those from people who were still living, stitching the remaining pedigrees together.
The data set, called the SAP for "set of aggregated and anonymized pedigrees," included almost 500 million individuals (with a single pedigree accounting for over 400 million people), largely Americans of European descent, each connected to another by either a parent-child or a spouse-spouse relationship. The scale of the data allowed the researchers to get accurate heritability estimates across different contexts; they could stratify the data by birth cohort or by sex or by other variables without losing the power needed for their analyses.
Running the numbers, the team initially found heritability estimates to be between 15-30% - similar to the reported literature. But genetics aren't the only thing that can be passed down between generations: sociocultural factors can also influence certain traits, and these too can be inherited. The combination of genetic heritability and sociocultural heritability is the total transferred variance, that is, the total amount of variability in a trait that can be explained by inheritance. Researchers looked not only at siblings-in-law and first cousins-in-law but also examined correlation in both types of co-siblings-in-law. None of these relationship types generally share household environments, and yet their life spans showed correlation.
If they don't share genetic information and they don't share household environment, what accounts for the similarity in life span between individuals within these relationship types? Going back to their impressive dataset, the researchers were able to perform analyses that detected assortative mating. In other words, people tend to select partners with traits like their own - in this case, how long they live. Of course, you can't easily guess the longevity of a potential mate, but the basis of this mate choice could be genetic or sociocultural - or both. For a non-genetic example, if income influences life span, and wealthy people tend to marry other wealthy people, that would lead to correlated longevity. By correcting for these effects of assortative mating, the new analysis found life span heritability is likely no more than seven percent, perhaps even lower.
Estimates of the Heritability of Human Longevity Are Substantially Inflated due to Assortative Mating
Human life span is a phenotype that integrates many aspects of health and environment into a single ultimate quantity: the elapsed time between birth and death. Though it is widely believed that long life runs in families for genetic reasons, estimates of life span "heritability" are consistently low (∼15-30%). Here, we used pedigree data from Ancestry public trees, including hundreds of millions of historical persons, to estimate the heritability of human longevity.
Although "nominal heritability" estimates based on correlations among genetic relatives agreed with prior literature, the majority of that correlation was also captured by correlations among nongenetic (in-law) relatives, suggestive of highly assortative mating around life span-influencing factors (genetic and/or environmental). We used structural equation modeling to account for assortative mating, and concluded that the true heritability of human longevity for birth cohorts across the 1800s and early 1900s was well below 10%, and that it has been generally overestimated due to the effect of assortative mating.
Senolytic Therapeutics Uses Nanotube-Carried Toxins to Destroy Senescent Cells
Today, I'll point out an analysis from the SENS Research Foundation that covers the approach to selective destruction of senescent cells taken by one of the newly formed biotech startups in the space, Senolytic Therapeutics. This field is hot because it is now well proven that senescent cells are the enemy. They are one of the root causes of aging, accumulating with age to degrade tissue function via the secretion of inflammatory signal molecules. Senescent cells actively maintain an aged, inflamed state of metabolism, resulting in the development of age-related disease and increased mortality.
Senescent cells do serve useful functions when they arise temporarily in response to injury or cell damage, so senescence as a phenomenon cannot be safely suppressed. Since the problems only begin when these cells both fail to self-destruct and evade the immune system's policing of tissues, however, finding ways to periodically destroy all lingering senescent cells is a very viable approach to rejuvenation. When they are removed from old tissues, aged metabolism is quite quickly restored to an incrementally younger state. This point has been quite adequately demonstrated in mice in recent years.
Roughly speaking, there are two approaches to the selective destruction of senescent cells. The first approach is to target a mechanism that is only significant in senescent cells, such as the fact that they are primed for self-destruction via apoptosis, and only held back by the thinnest of threads. A nudge to the apoptotic protein machinery that a normal cell will ignore will tip a senescent cell over the edge. The present crowd of senolytic pharmaceuticals fall into this category. The second approach is to use a therapeutic that will definitely kill any cell, senescent or not, and then limit its application to senescent cells only. Forms of immunotherapy and suicide gene therapy currently under development are examples of the type.
The staff at Senolytic Therapeutics are undertaking an interesting approach to the delivery of a standard chemotherapeutic means of killing cells in which nanotubes are used to ensure that only senescent cells are exposed to the toxin. The hollow nanotubes are filled with chemotherapeutic and capped with a molecule that only senescent cells will remove. Or at least only cells that express large amounts of senescence-associated beta-galactosidase, which might not be exactly the same thing, but the overlap is quite large. This is similar to a wide variety of approaches to targeting of specific cell populations developed in the cancer research community, and most of those are probably also applicable in principle to the task of clearing senescent cells from old tissues.
Smart Bombs Against Senescent Cells
When Dr. de Grey and colleagues proposed ablation of senescent cells (ApoptoSENS) as the "damage-repair" strategy of choice for this kind of aging damage in 2001, you'd've been hard-pressed to find the idea even mentioned (let alone advocated) in the scientific literature - and certainly no one was actively working to develop such therapies. This approach remained largely ignored until a powerful proof-of-concept study in 2011. Soon after that, researchers developed an ingenious drug-discovery strategy that led to the identification of the first two of a new class of "senolytic" drugs - that is, drugs that selectively destroy senescent cells.
In the three short years since the initial breakthrough discovery of the first senolytic drugs, the progress in ApoptoSENS has been astonishing. A torrent of scientific reports have now shown that ablating senescent cells has sweeping rejuvenative effects - wider-ranging, in fact, than we ourselves had predicted. Drugs and gene therapies that destroy senescent cells can restore exercise capacity, lung function, and formation of new blood and immune precursor cells of aging mice to nearly their youthful norms. Senolytic drugs and gene therapies have also ameliorated the side-effects of chemotherapy drugs in mice, and prevented or treated mouse models of diseases of aging such as osteoarthritis; fibrotic lung disease; hair loss; primary cancer and its recurrence after chemotherapy; atherosclerosis; and age-related diseases of the heart itself - as well as preventing Parkinson's disease and (very recently) frontotemporal dementia, a kind of cognitive aging driven by intracellular aggregates of tau protein, which are also an important driver of Alzheimer's dementia.
Scientists use a range of different cell markers to identify senescent cells: no one marker is infallible, and different senescence markers are more dominant in different senescent cell types. But the best-established and perhaps most universal sign of all is the activity of an enzyme called senescence-associated beta-galactosidase, or SA-beta-gal. To create a system that would release of cell-destroying drugs selectively in cells with senescent-cell levels of SA-beta-gal, chemists and nanotechnologists turned to an established platform for the selective delivery of drugs: mesoporous silica nanotubes, or MSNs. What makes MSNs so useful as drug-delivery systems is that their constituent tubes can be packed with any number of different drugs, and their openings on the surface of the nano-balls "capped" with molecular stoppers that keep the drug sealed inside until the MSN encounters chemical or other conditions that can break open the seal. So the trick is to identify a molecular stopper that is sensitive to chemical or physical conditions that are found in the type of cell that you want to target, and not found in innocent cells that you want to leave alone.
SA-beta-gal's actual function in the cell is to breaks down the sugar galactose: senescent cells just produce a whole lot more of it than normal cells. So to target MSNs to senescent cells, the team used galactooligosaccharide (GOS) as the stopper molecule - that is, a series of galactose molecules strung together in a chain. The researchers predicted that with their overabundance of SA-beta-gal, senescent cells would whittle down the chain of galactose molecules until they uncapped the MSNs and released their payload, while the same MSNs would pass through normal cells with their contents still safely sealed up. To test this, the team first drove several lines of cancer cells senescent using palbociclib, a cancer drug that works by shutting down genes that cancer cells require for cell division. They loaded up their GOS-MSN with doxorubicin, a toxic chemotherapy drug that is lethal to normal, cancerous, and senescent cells alike. An additional useful feature of doxorubicin is that it's intrinsically fluorescent, allowing the scientists to easily see where it was released.
GOS-MSN loaded with doxorubicin (DOX-GOS-MSN) passed harmlessly through three non-senescent cancer cell lines, and only released their payload in a small percentage of cells of the same lines that were exposed to palbociclib too briefly to induce widespread senescence. But when cancer cells were exposed to palbociclib for long enough to force them into senescence en masse, they lit up with doxorubicin fluorescence, and programmed cell death raged through the population.
Previous research had already shown that a variety of ApoptoSENS strategies can prevent or reverse idiopathic pulmonary fibrosis (IPF) in mouse models of the disease, as well as reversing the "normal" loss of lung function with age. The team wanted to see if DOX-GOS-MSN could similarly restore lung function in mice with a model of IPF. After first confirming that GOS-MSN distributed evenly across normal and senescent lung tissue they treated mice with either straight doxorubicin or DOX-GOS-MSN for two weeks, starting two weeks after inducing model IPF. Lung dysfunction scores remained stubbornly high in animals treated with plain doxorubicin, but DOX-GOS-MSN restored the lung function of the IPF model mice levels equivalent to young mice not subjected to lung damage. DOX-GOS-MSN also reduced the amount of fibrotic tissue in the animals' lungs, which untargeted doxorubicin was again unable to do.
With those exciting results in hand, the researchers have launched a biotech startup to turn GOS-MSN into a human rejuvenation biotechnology. Senolytic Therapeutics projects that that their therapies will be efficacious in treating multiple disorders which are caused and driven by the accumulation of damaged cells - that is, exactly the conditions that GOS-MSN treated so successfully in their recent proof-of-concept scientific report.
Jim Mellon Donates 100,000 to the SENS Research Foundation Year End Fundraiser
Today's good news is that investor Jim Mellon has provided a sizable charitable donation to the SENS Research Foundation in support of their advocacy and rejuvenation research programs. The foundation is currently running their year end fundraiser, and this certainly helps to move the needle towards the goal: I hope that other high net worth individuals take note. The rest of us should also take note! The SENS Research Foundation has succeeded in the past, has helped to advance the field, change the public debate on aging, and move important research from academic lab to clinical development, all as a result of our material support. Collectively, we provided the fuel to power this engine. If we want to see more and better progress towards human rejuvenation in the years ahead, then we must continue to put our shoulders to the wheel and provide the resources needed. Nothing in this world happens without effort, and that effort requires funding.
Accordingly, Josh Triplett, Christophe and Dominique Cornuejols, and Fight Aging! are matching the next year of donations made by any new SENS Patrons who sign up to make a monthly donation to the SENS Research Foundation. Two thirds of our 54,000 matching fund remain to be claimed. Donate today!
The SENS Research Foundation staff and the researchers in laboratories supported by SENS Research Foundation grants are presently hard at work on a range of ways to repair the molecular damage that causes aging, focusing on important areas that are are languishing, both poorly funded and given too little attention by the broader research community. Until comparatively recently that category included work on senescent cells, but now the development of senolytic therapies to destroy those harmful, unwanted cells in order to produce rejuvenation is a rapidly growing, very exciting area of medical biotechnology.
There are many other portions of aging research that could just as readily bloom into sizable medical industries, and just as rapidly given the technology and the proof of concept studies. The goal of the SENS Research Foundation is to enable those starting conditions for each and every one of the known root causes of aging, the forms of cell and tissue damage that ultimately lead to disability, disease, and death. There is tremendous potential in aging research, but all too little of the field is given the resources it merits, when considering the scale of the benefits that can result from the advent of real, actual, working rejuvenation therapies.
That so much of the potential for rejuvenation biotechnology is poorly funded and ignored means that we must step up to do our part. It means that all of the earliest and most important medical research is funded by philanthropy: the radical new directions; the high risk / high reward chances; the promising work for which the tools are lacking. In all such cases the established and very conservative sources of funding shirk their duty. Only philanthropists with a vision for a better future are willing to step up to make the difference. Everything starts with philanthropy, with charitable donations made to those organizations like the SENS Research Foundation that have a proven track record of doing the right thing.
Don't stand on the sidelines. Step up and help us to build a future in which the suffering and death of aging can be prevented or turned back, in which the old are hale and healthy and productive.
The Milken Institute's Longevity Innovators Interviews
The Milken Institute has published a set of interviews with a variety of scientists and non-scientists on topics of human longevity. A few these are of interest to those of who would like to see a fast path to rejuvenation therapies unfold in the years ahead. Some of the others illustrate a point I made last week, which is that while all that really needs to happen in this field is for the biotechnologies of rejuvenation to be developed, and as quickly and directly as possible, there are those who feel that the sociological aspects of human longevity must be talked to death in advance. Thus broader advocacy initiatives tend to pull in all sorts of figures who have nothing useful to say about the practical challenges of funding and developing rejuvenation therapies, but who are instead more concerned with how people feel about the topic, or the reaction of the endless rolling bane that is politics, or good health practices in the absence of rejuvenation therapies, or other line items that really, truly, do not matter at the end of the day.
If the therapies are built, the peoples of the world will quickly adapt, just as they have for any number of past revolutionary advances, and no-one will give much thought to all who felt that there should have been more discussion beforehand. If the therapies are not built, then we all suffer and die, and no-one will give much thought to all who felt that there should have been more discussion beforehand. The primary focus should be on the building, not the talking. This, of course, is not a popular point of view. One counterargument is that the sort of broad advocacy that involves a lot of talk that I'd consider largely irrelevant to the task at hand is in fact necessary in order to win the support of the public, or at least the largest and most conservative sources of funding, organizations that follow the tide of opinion makers rather than striking out in the right direction regardless. Whether or not this is the case is an interesting question, but larger advocacy initiatives all tend to proceed as though it were, and are arguably led by people who know a lot more about advocacy at scale than I do.
My impression of the past few decades of progress is that we started moving a lot faster once the first rejuvenation therapies were robustly demonstrated in the laboratory, but the details of that progress may or may not support my suggested view of the world above. In any case, I'll draw your attention here to the interviews with Laura Deming and Jim Mellon, both investors in the field of rejuvenation biotechnology, and the former a scientist who has studied aging in addition. As people who are helping to fund the research and development, they are among those who have interesting things to say on the topic. But do glance at the other interviews as well; you may find them interesting regardless.
Laura Deming: Healthspan, Not Lifespan
How can we make longevity an essential topic for potential investors?
I think that problem is actually already solved. People in the financial community, at least right now, are rapidly investing or interested in the space. That's the complete opposite of eight years ago, when nobody wanted to put capital into it. One thing that's been helpful is that companies either get access to the public markets or get started with less capital from well-earned means, and these two events have really raised the profile with the field. Going forward, I think what will be helpful is for longevity researchers to make better strides in science. I think the most important thing will be getting that first longevity-specific drug into the hands of patients. Once we see a drug from this area of science that actually produces a measurable benefit to patients that they could not have gotten otherwise, that will be the largest invite to new investors.
What do you think are the main reasons for scientists focusing on increasing healthy lifespan?
One big driver has been that nobody wants just to increase lifespan. It's nobody's idea of a good plan. It's kind of fascinating, because I think in the early days of the field, we didn't really understand what it was that we wanted to optimize for. But now it's very clear to everyone that we should be focusing on increasing the healthy part of the life, not just maximum lifespan in an old, decrepit state.
Jim Mellon: Investing in the Growing Longevity Market
Can you assess the current climate of longevity science? Is the market ready for this opportunity?
The market is now ripe for development. The excitement over rapalogs and senolytics, in particular, is helping, as is the prospect of the metformin trial, TAME. I expect that in the next year a lot of venture capital and possibly public funding will flow the way of longevity science. I think we are at about the internet of 1995 in terms of development.
How does the message of Juvenescence apply to nations that have yet to confront the challenges of population aging?
This will be one of the challenges of our age. Africa is the only place in the world where populations continue to grow rapidly. There is no reason why the life expectancy of Africans on average won't reach at least 100 within 30 years. Policymakers really need to drill down into this.
Are there other ways, besides taking your view of aging as a disease, that might increase government and corporate-funded research into aging?
Yes, we must improve our collective lobbying. The best way to do this is to point out the inevitability of pension scheme failures if governments don't recognize the ultra-longevity that is coming soon - and quickly.
How are younger workers affected when older employees remain on the job past the traditional retirement age?
The nature of work will have to change. As Joan Ruff of the AARP has said, older workers will not only be hired, they will be required. I believe that there will be plenty of work for all, it will just be different. Don't get caught up in the gloom of automation. Just be observant of trends.
Even Mild Hypertension is Harmful to Health
The scientific and medical communities have over recent years lowered the threshold of raised blood pressure that defines hypertension. This has happened due to increasing evidence for even lesser degrees of increased blood pressure to be notably harmful over the long term. There is apparently no such thing as a safe rise in blood pressure over the course of aging - any increase is damaging, and the greater the increase the greater the damage. The high blood pressure of hypertension harms delicate tissues, such as those of the kidney and brain, through mechanisms such as the rupture of capillaries. It also acts to accelerate the progression of atherosclerosis, and thus raise the risk of cardiovascular mortality via stroke and heart attack. The research noted here should not be surprising in this context, as it reveals that even the a pre-hypertensive state of somewhat raised blood pressure correlates with increased organ damage and dysfunction.
Hypertension is exacerbated by the usual problems of excess weight and poor diet, and that contribution at least is well within our ability to control, but even the best lifestyle choice can only slow the progression of molecular damage that stiffens blood vessels. When blood vessels cannot respond to circumstances by contracting or dilating to the appropriate degree, the evolved system of pressure regulation runs awry. Cross-links that form in the extracellular matrix impair elasticity; the elastin required for that elasticity diminishes with age; calcification takes place in old blood vessel walls; the smooth muscle cells become dysfunction for a variety of reasons. Therapies to address these issues lie somewhere in our future. Once introduced, they will have a sizable impact on human life expectancy via the prevention and reversal of hypertension.
Hypertension is a well-known risk factor for a variety of cardiovascular and renal diseases. Nowadays, it is estimated that more than 1 billion people have hypertension around the world. Furthermore, the prevalence of pre-hypertension, which is defined by a systolic blood pressure (SBP) from 120 to 139 mm Hg or a diastolic blood pressure (DBP) from 80 to 89 mm Hg, has also been dramatically increasing in recent decades. The Prospective Studies Collaboration, which included data from 61 observational studies, shows that for every 20/10 mm Hg increase in SBP and DBP, the risk of cardiovascular disease and mortality is increased two-fold, and this relationship extends to a BP level of 115/75 mm Hg. These data together imply that treatment of pre-hypertension should be beneficial for reducing target organ damage and cardiovascular events.
Arterial stiffness is a pathophysiological process of vascular ageing, and prior observational studies suggest that arterial stiffness is highly prevalent in subjects with hypertension. Nevertheless, the prevalence of arterial stiffness in subjects with pre-hypertension is unclear, and whether arterial stiffness is associated with target organ damage in subjects with pre-hypertension is also less well studied. Using data from a cross-sectional study, we evaluated the prevalence of arterial stiffness in subjects with pre-hypertension and potential risk factors for pre-hypertension. Moreover, whether arterial stiffness was independently associated with the prevalence of target organ damage including left ventricular hypertrophy and albuminuria in pre-hypertensive subjects was also evaluated.
The principal findings of our current study include four aspects. First, the prevalence of pre-hypertension in patients who came to the outpatient clinic for screening potential hypertension is 17.5% and the prevalence of target organ damage including left ventricular hypertrophy and albuminuria in subjects with pre-hypertension is not low. Second, compared to subjects without arterial stiffness, those with arterial stiffness are more likely to have left ventricular hypertrophy and albuminuria. Third, ageing and presence of arterial stiffness are two major potential risk factors for pre-hypertension. Fourth, in subjects with pre-hypertension, increased carotid-femoral pulse wave velocity is associated with higher prevalence of target organ damage such as left ventricular hypertrophy and albuminuria.
Extracellular NAD+ Declines with Age
Current enthusiasm for the development of means to boost levels of NAD+ in older people is driven in part by research such as the open access paper noted here, in which the authors show a clear decline with age in NAD+ outside cells. Inside cells, NAD+ is an important component in the machinery that allows mitochondria to generate chemical energy store molecules to power all cellular functions. Importantly, there is evidence that comparatively straightforward approaches to increase NAD+ levels can produce beneficial effects, such as improved mitochondrial function leading to lowered blood pressure via reduced dysfunction of smooth muscle cells in blood vessels, reducing blood vessel stiffness.
None of this is damage repair, rather a matter of putting damaged cells back to work, overriding one of the less helpful evolved responses to rising levels of molecular damage present in old tissues. The size of benefits is thus necessarily limited in comparison to approaches that can successfully repair the underlying damage that leads to reduced NAD+ levels and many other consequences. If the costs are low enough, then even limited benefits are worth chasing, however. It remains to be seen whether the cost-benefit considerations work out favorably in this case.
In the last decade, there has been growing interest in the role of redox active nucleotides in the metabolism. Nicotinamide adenine dinucleotide (NAD+) represents one of the most important coenzymes in the hydride transfer reactions. NAD+ is the precursor of the pyridine nucleotide family, including NADH, NADP+, and NADPH, and is the end product of tryptophan metabolism via the kynurenine pathway. It has been well established that NAD+ is a substrate for major dehydrogenase enzymes involved in nutrient catabolism. As well, NADH, which is the reduced form of NAD+, preferentially provides electrons to power mitochondrial oxidative phosphorylation. Apart from its roles in fuel utilization, NAD+ also serves as an exclusive substrate for nuclear repair enzymes.
NAD+ has also been shown to be the sole substrate for a new class of NAD-dependent histone deacetylase (HDAC) enzymes known as sirtuins. Increasing histone acetylation is associated with age-related pathologies, whereas gene silencing by upregulation of sirtuins has been shown to extend lifespan in yeast and small organisms. HDACs are also being found to interact with a variety of nonhistone proteins and to thereby change their function, activity, and stability by post-translational modifications. Accurate determination of the NAD+ metabolome is of major interest due to its potential association with cognitive decline, including AIDS dementia complex, cancer, aging, and a plethora of age-related disorders.
While it is thought that NAD+ is predominantly an intracellular nucleotide, emerging evidence suggests that extracellular NAD+ crosses the plasma membrane and replenishes intracellular NAD+. Accurate monitoring of the plasma NAD+ metabolome is necessary and may provide valuable information regarding the effect of various lifestyle and dietary factors, pharmacological and nutraceutical supplementation of NAD+ and/or its metabolites. We quantified changes in the NAD+ metabolome in plasma samples collected from healthy human subjects across a wide age range (20-87 years) using liquid chromatography coupled to tandem mass spectrometry. Our data show a significant decline in the plasma levels of NAD+, NADP+, and other important metabolites such as nicotinic acid adenine dinucleotide (NAAD) with age. Our data cumulatively suggest that age-related impairments are associated with corresponding alterations in the extracellular plasma NAD+ metabolome.
A Popular Science View of Checkpoint Inhibitor Cancer Immunotherapies
Checkpoint inhibitor therapies are a demonstrably successful approach to cancer immunotherapy. They suppress a mechanism that normally restrains immune cells from attacking other cells. This mechanism is abused by cancers, alongside a variety of other ways in which the immune system can be subverted or quieted. Any advanced tumor tends to have evolved into a state in which it is ignored or even helped by the immune system. Checkpoint inhibitor therapies are an improvement on chemotherapy when it comes to the trade-off between harming the cancer and harming the patient, as well as in the odds of success, but still present risks to patients. Immune checkpoints exist to prevent autoimmunity, and rampant autoimmunity can be just as deadly as any cancer.
Our usual defence against disease is our immune system. It does an excellent job of sorting out what doesn't belong in the body and attacking it - except when it comes to cancer. The checkpoint inhibitor breakthrough was the realisation that the immune system wasn't ignoring cancer. Instead, cancer was taking advantage of tricks that shut down the immune system. When stimulated, the T cell protein CTLA-4 acted like a circuit breaker on immune response. These brakes, which he called checkpoints, kept the cell killers from going out of control and trashing healthy body cells. Cancer took advantage of those brakes to survive and thrive.
In 1994, researchers developed an antibody that blocked CTLA-4. When they injected it into cancerous mice, the antibody jammed behind CTLA-4's brake pedal and prevented the T-cell attack from being stopped. Instead, the T-cells destroyed the tumours and cured the cancer. In 2011, that anti-CTLA-4 drug would gain approval as ipilimumab for use treating melanoma; it has since been approved to treat kidney and colorectal cancer. As a drug, it has saved many thousands of lives. Blocking the brakes on the immune system turned out to cause serious toxicities in some patients, but as a proof of concept, the success of ipilimumab proved that the immune system could, in fact, be weaponised against cancer. It also kicked off the search for newer, better immune checkpoints.
The first to be discovered was called PD-1. PD-1 is part of a sort of secret handshake that body cells give a T cell, telling it: "I'm one of you, don't attack." Cancers co-opted this secret handshake, tricking T cells into believing they were normal, healthy body cells. But that handshake could be blocked, creating a more precise cancer-killing machine with far fewer toxic side-effects than blocking CTLA-4. For many people, the anti-PD-1 drug pembrolizumab, approved in 2015 and sold as Keytruda, was the first and only thing they'd heard about cancer immunotherapy. Keytruda is currently one of the most widely used of the new class of drugs, approved for use against nine different types of cancer in the US, and a smaller number in the UK, and that list is growing rapidly.
Seven years after the approval of that first checkpoint inhibitor, there are reportedly 940 "new" cancer immunotherapeutic drugs being tested in the clinic by more than half-a-million cancer patients in more than 3,000 clinical trials, with over 1,000 more in the preclinical phase. Those numbers are dwarfed by the number of trials testing immunotherapy combinations or using them in concert with chemotherapy or radiation, which essentially turn the dead tumour into a cancer vaccine. It's hoped that, with checkpoint inhibitors releasing the brakes, the immune system can effectively finish up what the chemotherapy starts.
Does the Altered Blood Flow of Atrial Fibrillation Contribute to Dementia?
Given what we know of the relationship between hypertension and dementia, in which increased blood pressure damages the fragile tissues of the brain, causing loss of function over time, it is reasonable to consider that other disruptions of blood flow could have a similar relationship with the onset of dementia in later life. Researchers here investigate the association between atrial fibrillation and dementia, in search of specific disruptions in blood flow and brain tissue that could explain this relationship in terms of greater structural damage to the brain.
Researchers enrolled 246 patients in the study: 198 with atrial fibrillation and 48 without atrial fibrillation. They then obtained plasma samples and tested them for the circulating levels of four biomarkers associated with brain injury: glial specific GFAP and S100b; GDF15, a stress response marker; and neuron-specific tau protein. They found that levels of three of those biomarkers - tau, GDF15, and GFAP - were significantly higher in patients with atrial fibrillation. "We think patients with atrial fibrillation experience chronic, subclinical cerebral injuries. It becomes absolutely critical to identify the early markers of this injury and help these patients who are at higher risk of having subsequent neurodegenerative problems, such as cognitive decline and dementia."
Atrial fibrillation is an irregular and sometimes rapid heartbeat that can lead to blood clots, stroke, heart failure, and other heart-related problems. If people with atrial fibrillation are indeed suffering from ongoing brain injuries, they can also be at higher risk of developing everything from depression to neurodegeneration, which is the deterioration or death of the body's nerve cells, especially neurons in the brain, which could cause losses in mental function. That could be because atrial fibrillation alters blood flow through the body, including to and from the brain, which could lead to cerebral injury and disruption of the blood-brain barrier, which filters blood to and from the brain and spinal cord. If it's not working correctly, neuro-specific molecules like GFAP and tau get into the bloodstream, which was seen in this study.
The next step is to carry out the same kind of analysis on a larger group of patients. Recent results from the Swiss Atrial Fibrillation Cohort Study also point in the same direction - that atrial fibrillation causes brain injury. In the study, researchers performed MRIs on atrial fibrillation patients and found that 41 percent showed signs of at least one kind of a silent brain damage.
Klotho Shields the Brain from the Peripheral Immune System, but Declines with Age
Klotho is one of a number of well-known longevity-associated genes. The amount of klotho observed in tissues declines steadily with advancing age. Interventions that increase levels of klotho have been shown to slow measures of aging to some degree in animal studies. Beyond life span, klotho is also strongly associated with cognitive function. More klotho is better in this case as well. Artificially raised levels of klotho might one day be used as a form of enhancement therapy, capable of improving cognitive function even in younger people.
In the research noted here, scientists uncover one of the mechanisms linking falling levels of klotho to the impact of aging on the brain. Klotho helps to protect the brain from the activities of the immune system in the rest of the body, and when that protection falters, chronic inflammation can result. Inflammation is important in near all forms of neurodegeneration. In the view of aging as an accumulation of molecular damage, loss of klotho is a downstream consequence of that damage. Finding ways to deliver klotho to older individuals, boosting the amount in circulation, may well help with this one narrow outcome resulting from rising levels of cell and tissue damage. It remains the case that it would be far more effective to repair the damage, and thus remove all of the varied downstream consequences.
Curiously, within the brain, one structure contains vastly higher levels of klotho than all the others. This structure is the choroid plexus, which comprises a complex assembly of cells that produce cerebrospinal fluid and form an important barrier between the central nervous system and the blood. In a new study, researchers showed that klotho functions as a gatekeeper that shields the brain from the peripheral immune system. "We discovered, in mouse models, that klotho levels in the choroid plexus naturally decrease with age. We then mimicked this aging process by reducing levels of klotho in this structure experimentally, and we found that depleting this molecule increases brain inflammation."
The researchers further investigated the impact of this phenomenon on other brain regions. They discovered that in mice with less klotho in the choroid plexus, innate immune cells in an important memory center reacted more aggressively when other parts of the body were exposed to immune challenges that mimic infections. "The barrier between the brain and the immune system seems to break down with low levels of klotho. Our findings indicate that klotho helps keep that barrier closed. When levels of this molecule are depleted in the choroid plexus, the barrier becomes more porous and allows immune cells and inflammatory molecules to get through more easily."
"The molecular changes we observed in our study suggest that klotho depletion from the choroid plexus might contribute to cognitive decline in elderly people through brain inflammaging. It could help explain, at least in part, why we often notice deteriorations in cognitive functions in hospitalized seniors when they have infections, such as pneumonia or urinary tract infections. This complication tends to be particularly prominent in patients with Alzheimer's disease, in which inflammation has emerged as a major driver of pathology."
mTORC1 at the Intersection of Aging and Type 2 Diabetes
For the vast majority of patients, type 2 diabetes is caused by the presence of excess visceral fat tissue, and can be reversed even at a late stage by losing that fat tissue. The degree to which one needs to abuse one's own body in order to become diabetic falls with advancing age, however. Aging makes type 2 diabetes more likely to occur, all other factors being equal. Looking at the relationship from the other direction, the chronic inflammation and other forms of metabolic dysfunction characteristic of type 2 diabetes accelerates the progression of aging. The condition shortens life expectancy and is associated with greater incidence of the other common age-related conditions.
Researchers here consider mTORC1 as an important regulator of this two-way relationship between aging and type 2 diabetes. The complexes of mTOR, mechanistic target of rapamycin, have become well studied in recent years as a result of research into calorie restriction. mTOR is a master regulator of metabolism, involved in nutrient sensing and most of the subsequent processes that must adapt to varying levels of calorie intake. Inhibition of mTOR, or preferentially only the mTORC1 complex, is a way to partially mimic some of the beneficial results of calorie restriction. It provokes increased activity in stress response mechanisms, and the outcome, in animal studies at least, is improved health and extended healthy life span. Both aging and type 2 diabetes give rise to greater mTORC1 activity, and thus move things in the opposite, undesirable direction.
It is well known that insulin signaling is involved in the control of longevity in a wide spectrum of organisms including worms, flies, and mice. In addition, the use of rapamycin or knocking down mTOR can promote life extension in several species. During aging or under a hypercaloric diet exists an mTORC1 hyperactivity, which derives into a disruption in autophagy and, concomitantly an increase in endoplasmic reticulum (ER) stress. The overactivation of mTORC1 signaling specifically in pancreatic β cells leads to an augmented in β cell mass, which are related to hyperinsulinemia and hypoglycemia. However, chronic overactivation of mTORC1 signaling pathway develops a progressive hyperglycemia and a diminished islet mass.
Type 2 diabetes mellitus (T2DM) is a very complicated disorder. It is a progressive disease including insulin resistance, β-cell hyperplasia and/or β cell hypertrophy, that mediates a compensatory insulin secretion and subsequently hyperinsulinemia and pancreatic β cell dysfunction. At the insulin resistant prediabetic stage, mTORC1 is a key effector for the growth and survival of pancreatic β cells. However, if mTORC1 remains chronically overactivated, pancreatic beta cell death occurs and the compensatory insulin secretion mechanism it is compromised. Then, mTORC1 is a double-edged sword in the progression to T2DM.
Diabetes is a multifactorial and progressive disease with two phases; firstly, a prediabetic stage, with an insulin resistance and hyperinsulinemia, and secondly as manifest diabetes associated with hypoinsulinemia and hyperglycemia. Then, it is crucial to understand the transition from prediabetes to type 2-diabetes status and the underlying molecular mechanisms of disease. At this stage, chronic overactivation of mTORC1 signaling pathway in β islets from prediabetic patients leads to on one hand to the expansion of the pancreatic beta cell mass and, on the other to the inhibition of autophagy as protective mechanism of beta cells against the attack of several stressors, making these cells more prone to trigger apoptosis. Thus, the maintenance of a functional autophagy it is an essential component to protect and prolong pancreatic β cell life span precluding chronic hyperglycemia.
Growing Enthusiasm for the Development of Geroprotectors
A geroprotector is a drug or supplement that either slows the underlying causes of aging or produces a greater resistance to the damage of aging. In either case health is prolonged and mortality decreased. Calorie restriction mimetics are the best example of the type, but the category is expansive enough to include well known drugs such as aspirin. As you might imagine of a class of treatments that includes aspirin, the size of effect when it comes to additional years of life is fairly small, even in those cases in which the benefits are reliable. Geroprotectors largely work through upregulation of stress responses, something that has much larger effects in short-lived species, such as mice, than in long-lived species, such as our own.
Nonetheless, there is a growing interest in developing these compounds and bringing them to the clinic. Far more interest than is warranted, I'd say. If all of that attention was instead devoted to the SENS portfolio of approaches to rejuvenation, classes of therapy that are based on repair of the molecular damage that causes aging, then we might be moving a lot more rapidly towards reversal of aging and large gains in healthy life span, rather than towards the very modest, incremental slowing of aging that most research groups are aiming for. Repair and reversal will always be a much better approach to improving the function of complex machinery than a mere slowing of damage.
To confuse the nice neat line between two approaches to aging that I've drawn above, in the research here, the scientists are treating the senolytic compound fisetin as a geroprotector. It may well have effects that involve upregulation of stress responses, thus slightly slowing aging, but it would be hard to argue that those are large in comparison to its ability to destroy senescent cells, and thus reverse that cause of aging. That said, the senolytic dose is much larger than the usually explored dose, and so there may well be multiple mechanisms of interest involved.
Old age is the greatest risk factor for many diseases, including Alzheimer's disease (AD) and cancer. Geroprotectors are a recently identified class of anti-aging compounds. New research has now identified a unique subclass of these compounds, dubbed geroneuroprotectors (GNPs), which are AD drug candidates and slow the aging process in mice. "The argument for geroprotectors is that if one can extend the lifespan of model organisms, such as mice, and translate this effect to humans, then you should be able to slow down the appearance of many diseases that are associated with aging, such as Alzheimer's, Parkinson's, cancer and overall frailty."
The team started with two chemicals found in plants that have demonstrated medicinal properties: fisetin, a natural product derived from fruits and vegetables, and curcumin, from the curry spice turmeric. From these, the team synthesized three AD drug candidates based upon their ability to protect neurons from multiple toxicities associated with the aging brain. The lab showed that these three synthetic candidates (known as CMS121, CAD31 and J147), as well as fisetin and curcumin, reduced the molecular markers of aging, as well as dementia, and extended the median lifespan of mice or flies.
Importantly, the group demonstrated that the molecular pathways engaged by these AD drug candidates are the same as two other well-researched synthetic compounds that are known to extend the lifespan of many animals. For this reason, and based on the results of their previous studies, the team says fisetin, curcumin and the three AD drug candidates all meet the definition of being geroneuroprotectors. The group is now focusing on getting two GNPs into human clinical trials. The fisetin derivative, CMS121, is currently in the animal toxicology studies required for FDA approval to start clinical trials. The curcumin derivative, J147, is under FDA review for allowance to start clinical trials for AD early next year. The group plans to incorporate biochemical markers for aging into the clinical trials to assay for potential geroprotective effects.
Antihypertensive Use Correlates with Higher Epigenetic Age Despite Reduced Mortality
The best epigenetic clocks correlate well with chronological age, and when the measure departs from chronological age, that difference correlates well with risk or incidence of age-related disease. A higher epigenetic age is seen in people known to have higher age-related morbidity and mortality. The tantalizing potential offered by these clocks is the ability to quickly determine whether or not a putative rejuvenation therapy actually works, and to what degree it works. A true, rapidly assessed, cheap marker of biological age would greatly accelerate research and development. Unfortunately, this goal remains elusive because it is very unclear as what exactly the clocks are measuring. Yes, they measure changes in specific epigenetic markers, but which of the myriad processes involved in aging cause those epigenetic changes? If researchers cannot answer that question, then it is very hard to derive any useful information from epigenetic clocks.
The open access paper here is a good illustration of this point. Researchers checked the epigenetic age of hypertensive patients, both those using antihypertensive medication and those who did not use the medication. One would expect to see a reduction in epigenetic age, given that (a) the raised blood pressure that occurs with aging is highly damaging to delicate tissues, and (b) even blunt pharmaceutical means of reducing blood pressure, that fail to address the root causes and instead forcefully override cellular reactions, reduce mortality and incidence of age-related disease. Instead, researchers found that patients using antihypertensive medications had a higher epigenetic age. What are we to make of this result? The challenge, again, is that there is no good answer to that question.
DNA methylation, a major form of epigenetic modification, is known to play an important role in aging and the development of age-related health outcomes. Recently, a DNA methylation-based biological age predictor, "DNA methylation age (DNAmAge)", has been established and found to be highly associated with chronological age. The discrepancy between this epigenetic-based indicator and the chronological age has been termed age acceleration (AA), which was found to be heritable and has been used as an index of accelerated biological aging.
Several aging-related factors, including inflammation, neurohormonal disorder, and endothelial dysfunction, have been found to play key mechanistic roles in the development of hypertension, the most common long-term medical condition among older adults that could lead to various forms of age-related health outcomes, such as cardiovascular diseases (CVD), kidney failure, and dementia. Relationships of hypertension and blood pressure with biological aging have also been studied since the introduction of DNAmAge. In 2016 it was found that people with hypertension had a higher AA (0.5 - 1.2 years) in comparison to controls.
The use of antihypertension medication (AHM) reduces the risk of adverse age-related health outcomes caused by hypertension. Specifically, observational studies, clinical trials, and systematic reviews mostly suggested that effective antihypertensive therapy greatly reduces the risk of CVD in patients with hypertension, and may also be associated with a decreased risk of cognitive decline and incident dementia. As DNA methylation is a durable and reversible modification, we hypothesized that the use of AHMs might also be able to influence the biological aging reflected by the epigenetic AA. Therefore, we assessed the associations of AHM use with AA and further determined whether the change of AHM use could modify the change rate of AA (ΔAA).
After the fully adjusting for potential covariates including hypertension, any AHM use showed a cross-sectional significant association with higher AA at each visit, as well as a longitudinal association with increased ΔAA between visits. Particularly, relative to participants who never took any AHM, individuals with continuous AHM use had a higher ΔAA of 0.6 year/chronological year. This finding underlines that DNAmAge and AA may not be able to capture the preventive effects of AHMs that reduce cardiovascular risks and mortality.
Initial Evidence for the Antibiotics Azithromycin and Roxithromycin to be Senolytic
Researchers here report on two new senolytic compounds identified in the existing library of approved drugs, based on screening work in cell cultures. It is worth bearing in mind that drug candidates that demonstrate good results in cell culture quite often fail to show promise when tested in animals, so it is wise to be patient as new senolytics work their way through the research and development pipeline.
There will be a lot more of this sort of thing in the years ahead, as ever greater amounts of funding pour into finding new ways to selectively destroy senescent cells. Any senolytic approach that removes a significant fraction of these cells will produce a degree of rejuvenation in older patients, and so the hunt for mechanisms has taken on something of the air of a gold rush. So far at least four different mechanisms for prompting the self-destruction of senescent cells are targeted by a dozen or more drug candidates, while immunotherapy and suicide gene therapy approaches also exist. This will be a very busy industry a few years from now, and that bodes well for the future of our health and longevity.
Senescence is a clear hallmark of normal chronological aging. Senescence involves potentially irreversible cell cycle arrest, via the induction of CDK-inhibitors, such as p16-INK4A, p19-ARF, p21-WAF and p27-KIP1, as well as the onset of the SASP (senescence-associated secretory phenotype), and the induction of key lysosomal enzymes (e.g., Beta-Galactosidase) and Lipofuscin, an established aging-pigment. Interestingly, SASP results in the secretion of a wide array of inflammatory cytokines, such as IL-1-beta and IL-6, allowing senescent cells to "contagiously" spread the senescence phenotype from one cell type to another, systemically throughout the body, via chronic inflammation. Such chronic inflammation can also promote the onset of cancer, as well as drive tumor recurrence and metastasis.
Using the promoter of p16-IN4KA as a transgenic probe to detect and mark senescent cells, several research groups have now created murine models of aging in which senescent cells can be genetically eliminated in a real-time temporal fashion. Although this cannot be used as an anti-aging therapy, it can give us an indication whether the removal of senescent cells can potentially have therapeutic benefits to the organism. Results to date show great promise, indicating that the genetic removal of senescent cells can indeed prolong healthspan and lifespan.
As a consequence of this exciting genetic data, a large number of pharmaceutical companies are now actively engaged in the discovery of "senolytic" drugs that can target senescent cells. However, we believe that many FDA-approved drugs may also possess senolytic activity and this would dramatically accelerate the clinical use of these senolytic drugs in any anti-aging drug trials. Here, we have used controlled DNA-damage as a tool to induce senescence in human fibroblasts, which then can be employed as an efficient platform for drug screening.
Using this approach, we now report the identification of two macrolide antibiotics of the Erythromycin family, specifically Azithromycin and Roxithromycin, as new clinically-approved senolytic drugs. In direct support of the high specificity of these complex interactions, the parent macrolide compound - Erythromycin itself - has no senolytic activity in our assay system. Interestingly, Azithromycin is used clinically to chronically treat patients with cystic fibrosis, a genetic disease of the chloride-transporter, that generates a hyper-inflammatory state in lung tissue. Azithromycin extends patient lifespan by acting as an anti-inflammatory drug that prevents the onset of lung fibrosis by targeting and somehow eliminating "pro-inflammatory" lung fibroblasts. Therefore, the efficacy of Azithromycin in cystic fibrosis patients provides supporting clinical evidence for our current findings, as these lung fibroblasts are pro-inflammatory most likely because they are senescent.
USP13 Inhibition Clears Lewy Bodies in a Mouse Model of Parkinson's Disease
Many age-related conditions are associated with solid aggregates in tissues that are formed of altered, damaged, or misfolded proteins. Protein aggregates are thought to be an important contributing cause of these diseases. In most cases the proteins involved in aggregate formation can and do appear in lesser amounts in young tissues, but we can point to underlying problems that might explain why aggregates only appear in significant amounts in old tissues. Failure of clearance via fluid flow or the actions of immune cells for intracellular aggregates, or failure of clearance via autophagy within cells, for example. Near all processes in cellular metabolism falter with age, and increasing amounts of molecular waste is one of the many detrimental consequences.
Aging is in some ways a garbage catastrophe, and removal of aggregates is an important strategy for the treatment of aging as a medical condition. This has unfortunately proven to be a challenging task, particular for those aggregates that form primarily in the brain. The Alzheimer's research community required decades and a great deal of funding to get to the point of even preliminary success in the removal of amyloid-β via immunotherapies, for example. In the case of Parkinson's disease and α-synuclein aggregates, the situation is much the same: slow progress. Thus all novel possibilities for the removal of aggregates associated with neurodegenerative disease should be warmly welcomed.
A defining feature of Parkinson's disease is the clumps of alpha-synuclein protein that accumulate in the brain's motor control area, destroying dopamine-producing neurons. Natural processes can't clear these clusters, known as Lewy bodies, and no one has demonstrated how to stop the build up as well as breakdown of the clumps - until perhaps now. A team of neurologists has found through studies in mice and human brains that one reason Lewy bodies develop is that a molecule, USP13, has removed all the "tags" placed on alpha-synuclein that mark the protein for destruction. Toxic heaps of alpha-synuclein accumulate, and are never taken away. The findings show that inhibiting USP13 in mouse models of Parkinson's disease both eliminated Lewy bodies and stopped them from building up again.
The "tag" that USP13 removes is called ubiquitin, which labels alpha-synuclein for degradation. Parkin is one of a family of ubiquitin ligase enzymes. Ubiquitination is a process in which molecules are labeled (or tagged) with ubiquitin and directed to cellular machines that break them down. USP13 is known as a de-ubiquitinating enzyme, which removes ubiquitin tags from protein. USP13 renders parkin ineffective via removal of ubiquitin tags (de-ubiquitination) from proteins. Loss of parkin function leads to genetically inherited forms of Parkinson's disease.
The study began with postmortem autopsies of individuals who donated their brains to research, including 11 with Parkinson's disease and a control group of 9 without Parkinson's. The autopsies, which occurred 4 to 12 hours after death, found that the level of USP13 was significantly increased in the midbrain in Parkinson's disease patients, compared to the control participants. Studies in mouse models of Parkinson's disease then demonstrated that knocking out the USP13 gene increased alpha-synuclein ubiquitination and destruction. Researchers also saw that USP13 knockdown protected the mice against alpha-synuclein-induced dopamine neuron death. The mice had improved motor performance; parkin protein was increased and alpha-synuclein was cleared.