Fight Aging! Newsletter, November 19th 2018

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."

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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."

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.

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.

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.

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.

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.