Fight Aging! Newsletter, December 23rd 2019

Good afternoon, everybody. I'm pleased to be here. I'm a cofounder of Juvenescence, along with Jim Mellon and Greg Bailey. Those two are the ones who put the company together and are raising all of the capital. I'm the one who spends it. We are ambitious: we can have a meaningful impact on health in the context of longevity. As you heard this morning, aging is a disease, and we want to embark on investigating the mechanisms in longevity, learning from what is going on around us, but also looking to solutions - because we're a drug development company. We're raising capital, we've done quite well so far, thanks to Jim and Greg, and thanks to some of the investors in this room. We want to get on with the job.

Now, I'm a physician. I qualified a long time ago, and looking around the room I could be the oldest person here - which is scary. But I'm involved in this because I think it is a huge medical and societal need. What was really of concern to me was when I saw the statistics. Of course we've done well, we're living longer, 30 years longer than a century ago, and that was usually due to public health measures and control of infectious disease, and so on. But longevity is becoming a huge issue because of the number of people living longer. A 60 year old male, if he is doing everything right, can get 13 years more life expectancy than non-healthy people. But we have 10 or 11 years of unhealth at the end of life, which I call disability in this slide. In the US it is about 11.5 years. In the UK and Japan, as you can see here, 10.8 years. As noted this morning, 25% of Medicare costs occur in the last year of life.

So you can see the opportunity here for the research, development, and medical communities do a lot of good. We have done good in terms of managing cardiovascular disease up to now, to a point. But hypertension causes 45% of all cardiovascular deaths, and it is rising. 80% of the elderly have hypertension, and screening is still not good enough, especially outside the US and Europe. We have the drugs: thiazide and ACE inhibitors are particularly good for reducing not just blood pressure, but cardiovascular events and associated mortality. As you know the statins have done pretty well in terms of managing cholesterol and cardiovascular events and mortality.

Now I put up this next slide not to blow a trumpet or anything, but to say that I am a product of two things. Firstly, I went to medical school to learn how to detect and manage disease. Secondly, I entered the drug industry in the small molecule era where we blocked receptors and enzymes because it translated into disease constructs that we could measure. You could drop blood pressure, you could cure bacterial infection, and also decrease blood cholesterol. So that was terrific at the time, but you also heard this morning about the rise of molecular biology, monoclonal antibodies, and now gene therapy. Where I was is now old school, but it did good, and it is still needed. I've done some other things in terms of small molecules and fatty acids, and the last one is Juvenescence. This is the one thing that will probably be my last hurrah, so to speak, but I'm going to hand off to our wonderful team of young people who are going to take the baton and run with this. They will deliver some of the medicines that we hope we can develop in the not so distant future.

So the first thing I asked myself is this: really, can aging be reversed? I've listened to Aubrey de Grey for a long time, and I'm now persuaded of that. I am also persuaded that aging is a construct that we all, as physicians and drug developers and whomever, should be passionate about fixing. I mean unhealthy aging. There are all these kinds of interventions and technologies that we can access, some of which will be extraordinary, and look like moonshots, while others will be more incremental. As was said this morning, there are other technologies that we need to be participant in: diagnostics, devices, apps, measurement of health management efficiency, and also we need to change our incentives.

In the American healthcare system, where I live, we are activity-based in terms of incentives. We get rewarded for identifying and treating disease. We do not get rewarded for identifying healthy people and keeping them healthy. So we have to change those incentives. Someone might say "where's the money for a drug company in keeping people healthy rather than treating disease?" But we have to migrate to that new model.

There are drugs in development that have been mentioned this morning. I think Reason mentioned the senolytic dasatinib, that has been used and has impact on longevity. A paper from Intervene Immune described the use of growth hormone, DHEA, metformin, and vitamin D to actually increase longevity. And you might say "how do you do that" - well you measure it by the aging clock, the Horvath epigenetic clock. Then Unity Biotechnology is developing a senolytic for osteoarthritis and pulmonary fibrosis. resTORbio is developing a rapalog for the treatment of immunosenescence; our immune system declines in its efficiency as we get older, manifesting in other diseases coming through. What they've done was a very clever thing, they looked at the uptake of flu vaccine in an elderly cohort, there is an antigen response, and showed that it protected more than in the control group in terms of susceptibility to disease. Samumed, working on the Wnt pathway, treating osteoarthritis of the knee. Then we have MitoQ, nicotinamide riboside, and cell therapy with Mike West's AgeX Therapeutics.

But in order to get there, we don't just say "hey, we've got a disease modifier." Or an age-modifier. We actually access it through disease constructs, as Nir Barzilai has for the TAME metformin trial. These are the sorts of areas where I think I can help design programs with the new technologies and measure impact in a biomarker-enabled way. Then we have that dialog with the FDA, and Europeans, and other agencies, to at least get them to buy into the idea that you are doing something that might improve the prospects for patients, that can manifest in a longer but healthier life. My view is that if you can compress that time of disability from even 11 to 10 years, the benefits to society will be massive.

What we're trying to do at Juvenescence is develop these treatments for both prevention and reversal. I wasn't sure that was going to be possible, until I saw some of the preclinical basic data. We really want to build a thriving company; we have a great group of young people - and young to me is something less than 40 - who are embarking on search and diligence, and we've got an emergent drug development team who are expert and experienced in developing drugs in the conventional pharma model. So we know how to deal with regulators and dialog with them, because we've had plenty of experience of what I'll not call misunderstandings, but miscommunication and misalignment of expectations. What we hope to do is to participate with other companies in moving the agenda forward such that the regulators are understanding that we're all trying to do something of merit, and they have got to work with us to regulate in a practicable way.

In the next slide, I think Laura Deming showed the left picture, of middle-aged mice, on how altering the genome can lead to a longer healthy life span and a change in the phenotype of the patient. This on the right is another set of mouse pictures, and this is from a company that we've invested in that actually interacts with the FOXO4-p53 system. And you look, that is an aged mouse, and the treatment perturbed that FOXO4-p53 system, and you do get rejuvenation. So maybe there is one clue to what we might be able to do in humans, and we're developing drugs in that space. I would hope to see that there is at least a modicum of translation from these animal models. Some animal models will not translate, and we'll learn with the passage of time. But these are the experiments that we'll have to do, and we'll learn from one another.

There is another company that we have, Lygenesis, which is probably the most advanced in terms of bringing something to the clinic. This is organ regeneration, a wonderful little company from Pittsburgh. They actually take hepatocytes and inject them into the abdominal lymph nodes. The hepatocytes are engineered and they grow ectopic livers. This has been shown in dogs: it does actually work, and we're preparing to go into the clinic in humans. Why are we doing that? First of all, the number of liver transplants in a year in the US is now about 8,000 and it is about to grow dramatically because of the increased incidence of nonalcoholic steatohepatitis and cirrhosis, and so on. Each transplant costs 700,000. If you multiply that by 8,000, and going up, you have a big price tag that you've got to pay for healthcare. If Lygenesis could mitigate some of those transplants, you will have a benefit that is quite easy to understand. We were showing that this is a company that is barreling along the road to the clinic, and I have to say that they are a fantastic team of people.

Now, just in finishing up, I want to say that we are a drug development company. We have capital, and Jim and Greg are raising more. We see great opportunities. We are, I won't call it agnostic, but we have a very broad purview over technologies that might actually bear fruit. We have a very good search and diligence team, who set a high bar. We don't just take in anything. We have an ecosystem of longevity experts and drug development experts we can bring to bear. When there is a company that we acquire or a technology we acquire, we fill the gaps. So although we've got the capital to invest, we are principally a drug development company.

The other point I mean is that when I was talking about health, in the future we are not talking about patients. I believe that we should be talking about pre-patients. All of you here who don't have a disease, and you want not to get it, there should be some strategy that you adopt for yourselves, and indeed for your family. When do you start? Now is a good time to start managing the parameters that you know predict for ill health. We go to our annual physician checkup - in this country I've been to many of them, and they are not all that good. I think that we really need to up our game in screening. To have broader biomarkers that we actually incorporate into our annual health screening, and which should be personalized. Our genetics are different, so our propensities are different. So a degree of personalized prevention I think is where we should be headed as well, to manage these growing healthcare costs.

Finally, in our company, we are ambitious, we think we can do it. We've got a lot of companies under our purview now, and we're going to acquire more. We'll need more capital and eventually we'll IPO. Thank you very much.

Hematopoietic stem cell (HSC) aging was originally thought to be essentially an HSC-autonomous process. However, studies on the microenvironment that maintains and regulates HSCs (the HSC niche) over the past 20 years have suggested that microenvironmental aging contributes to declined HSC function over time. The HSC niches comprise a complex and dynamic molecular network of interactions across multiple cell types, including endothelial cells, mesenchymal stromal cells (BMSCs), osteoblasts, adipocytes, neuro-glial cells and mature hematopoietic cells.

Upon aging, functional changes in the HSC niches, such as microenvironmental senescence, imbalanced BMSC differentiation, vascular remodeling, changes in adrenergic signaling, and inflammation, coordinately and dynamically influence the fate of HSCs and their downstream progeny. The end result is lymphoid deficiency and myeloid skewing. During this process, aged HSCs and their derivatives remodel the niche to favor myeloid expansion. Therefore, the crosstalk between HSC and the microenvironment is indispensable for the aging of the hematopoietic system and might represent a therapeutic target in age-related pathological disorders.

Hematopoietic stem cells (HSCs) are sustaining blood production during the whole life of an organism. It is of extreme importance that these cells maintain self-renewal and differentiation potential over time, in order to preserve homeostasis of the hematopoietic system. Many HSC intrinsic aspects are affected by the aging process, leading to the deterioration of the potential of these cells independently of their microenvironment. Here we review recent findings characterizing most of the intrinsic aspects of aged HSCs, ranging from phenotypic to molecular alterations.

Historically, DNA damage was thought to be the main responsible for HSC aging. However, in the last years, many new findings have defined an increasing number of biological processes that are intrinsically changing with age in HSCs. Epigenetics and chromatin architecture together with autophagy, proteostasis, and metabolic changes and how they are interconnected to each other are acquiring growing importance for understanding the intrinsic aging of stem cells. Considering that aging is the primary risk factors for most diseases, understanding HSC aging becomes particularly relevant as well in the context of hematological disorders, such as myelodysplastic syndrome and acute myeloid leukemia. Research on intrinsic mechanisms responsible of HSC aging is and will continue to provide new potential molecular targets to possibly ameliorate or delay aging of the hematopoietic system and consequently improve the outcome of hematological disorders in the elderly.

Macroautophagy (hereafter called autophagy) facilitates degradation and recycling of cytosolic components, referred to as cargo, in response to nutrient deprivation or other stressors. Autophagy is initiated by the nucleation of a double membrane, which forms the phagophore. As the phagophore expands, it begins to sequester cytosolic cargo into the growing vesicle. Upon completion, the autophagosome or amphisome (formed by fusion with vesicles from the endolysosomal compartments) then fuse with acidic lysosomes, resulting in the degradation of the sequestered content by hydrolases.

Autophagy is essential for survival, development, and organismal homeostasis. It occurs at low levels under basal conditions, whereas developmental stimuli or cellular stress, including starvation and heat shock, can induce autophagy. Furthermore, autophagy can protect against pathologies, including neurodegeneration and aging. The regulation of autophagy with age is incompletely understood, but several lines of evidence suggest that autophagy declines with age. Conversely, autophagy genes are essential for lifespan extension in distinct longevity paradigms in S. cerevisiae, C. elegans, and Drosophila. While these observations demonstrate a link between autophagy and aging, it remains unclear how the autophagy process affects longevity and healthspan.

Autophagy was originally described as a 'bulk' turnover process, in which cytosolic components are indiscriminately recycled to provide amino acids and other building blocks during nutrient deprivation and cellular stress. Emerging evidence indicates that selective types of autophagy degrade specific and possibly damaged cytosolic components in a tightly regulated manner. During selective autophagy, autophagosomes recruit specific types of cargo, including mitochondria and protein aggregates, through the action of autophagy receptors that connect the autophagosome to the cargo. The selective autophagic degradation of ubiquitinated protein aggregates, termed aggrephagy, can be facilitated by autophagy receptor p62/SQSTM1 (hereafter referred to as p62).

The degradation of ubiquitinated proteins can occur via autophagy as well as the ubiquitin-proteasome system (UPS), and p62 has been implicated in both processes; i.e., as a selective autophagy receptor, and through the delivery of ubiquitinated proteins for degradation to the proteasome. Consistent with a key role in age-related disease, mice deficient in p62 have reduced lifespan, increased oxidative stress, synaptic deficiencies, and memory impairment. The expression levels of p62 have been shown to decline with age in mice, and reduced expression of p62 correlates with age-related neurodegenerative diseases in humans. Notably, we recently reported that sqst-1 mRNA levels are markedly increased upon heat stress in C. elegans, prompting the hypothesis that SQST-1 may play a role in the heat-shock response, in which heat-shock proteins and molecular chaperones are rapidly and transiently induced to ameliorate the deleterious effects of heat stress.

Since emerging evidence suggests that the degradation of specific cargos by selective autophagy is important for maintaining health, we investigated the role of SQST-1 in hormetic heat shock, lifespan, and proteostasis. Here we demonstrate that sqst-1 is required for autophagy induction as well as organismal benefits conferred by a hormetic heat shock. Furthermore, we show that overexpression of SQST-1 is sufficient to increase longevity in C. elegans. SQST-1 overexpression leads to tissue-specific induction of autophagy. These observations illustrate that overexpression of a selective autophagy receptor is sufficient to induce autophagy and enhance longevity and proteostasis. As p62 plays an important role in many age-related diseases, our findings highlight the potential for therapeutic opportunities in inducing p62-mediated selective autophagy.

Human life expectancy worldwide rose dramatically over the past century, but people's health spans - the period of life spent free from chronic, age-related disease or disability - have not increased accordingly. "Twenty-first century medicine should adopt the strategy of directly targeting the molecular mechanisms that cause biological aging. Only in this way will it be possible to slow the onset and progression of multiple age-related diseases simultaneously, in order to extend the health span proportionately with the life span." The authors write that aging itself is not a disease, but rather is the biggest risk factor for a wide range of chronic diseases. This is a central tenet of the emerging field of geroscience, which seeks to define the biological mechanisms that underly the diseases of aging - with the goal of slowing human aging to delay or prevent many diseases simultaneously.

Biomedical research and clinical practice have traditionally been focused on disease rather than health. We typically wait until people are sick before trying to cure their disease or alleviate their symptoms, rather than actively supporting health and wellbeing in the absence of disease. Current demographic trends toward older populations make this approach problematic. Instead of improving the quality of life, we may be extending the period of morbidity and frailty for millions of people. Twenty-first century medicine should adopt the strategy of directly targeting the molecular mechanisms that cause biological aging. Only in this way will it be possible to slow the onset and progression of multiple age-related diseases simultaneously, in order to extend the healthspan proportionately with the lifespan.

The language of the longevity dividend as we know it today originated in 2006, but its intellectual origins are not new. in 1956 Clive McKay suggested the successful life extension that had already been achieved in laboratory animals by then (without knowing whether changes in the healthspan also occurred in these animals) justified the experimental manipulation of the lifespan in humans. A lot has happened in the past 65 years since this idea first appeared and in the 13 years since the term was first used. Just recognizing that aging itself is inherently modifiable, and that interventions derived from aging biology represent a new, more promising form of primary prevention than the usual approach to treating one disease at a time, is sufficient reason to see the value of the modern rise of geroscience and the longevity dividend initiative. The language of these initiatives has now made its way into mainstream medicine, in the form of a preference for "healthspan" over "lifespan", representing a new meme that should permanently change the way in which humanity thinks about what it means to age.

Alzheimer's disease is a growing threat to the economic and social well-being of developed countries around the globe, but efforts to delay, prevent, or cure this disorder have yet to yield success. I believe the lack of progress largely results from approaches that ignore the most important component of Alzheimer's disease: biological aging. Major advances have been made in understanding the molecular mechanisms that link biological aging to disease. These mechanisms have been formalized as nine hallmarks, or pillars, of aging. Here, I discuss the barriers that have impaired progress and propose specific steps that can be taken to overcome these barriers. The time has come to adopt bold new strategies that tackle biological aging as the root cause of Alzheimer's disease.

Researchers analyzed the levels of proteins circulating in plasma - the cell-free, fluid fraction of blood - from 4,263 people ages 18-95. On measuring the levels of roughly 3,000 proteins in each individual's plasma, researchers identified 1,379 proteins whose levels varied significantly with participants' age. A reduced set of 373 of those proteins was sufficient for predicting participants' ages with great accuracy. In fact, a mere nine proteins were enough to do a passable job, and adding more proteins to the clock improves its prediction accuracy only a bit more.

The study's results suggest that physiological aging does not simply proceed at a perfectly even pace, but rather seems to chart a more herky-jerky trajectory, with three distinct inflection points in the human life cycle. Those three points, occurring on average at ages 34, 60 and 78, stand out as distinct times when the number of different blood-borne proteins that are exhibiting noticeable changes in abundance rises to a crest. This happens because instead of simply increasing or decreasing steadily or staying the same throughout life, the levels of many proteins remain constant for a while and then at one point or another undergo sudden upward or downward shifts. These shifts tend to bunch up at three separate points in a person's life: young adulthood, late middle age and old age.

The investigators built their clock by looking at composite levels of proteins within groups of people rather than in individuals. But the resulting formula proved able to predict individuals' ages within a range of three years most of the time. And when it didn't, there was an interesting upshot: People whose predicted age was substantially lower than their actual one turned out to be remarkably healthy for their age.

Aging is a predominant risk factor for several chronic diseases that limit healthspan. Mechanisms of aging are thus increasingly recognized as potential therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues, which supports a hypothesis that age-related molecular changes in blood could provide new insights into age-related disease biology. We measured 2,925 plasma proteins from 4,263 young adults to nonagenarians (18-95 years old) and developed a new bioinformatics approach that uncovered marked non-linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh and eighth decades of life reflected distinct biological pathways and revealed differential associations with the genome and proteome of age-related diseases and phenotypic traits. This new approach to the study of aging led to the discovery of unexpected signatures and pathways that might offer potential targets for age-related diseases.

Scientists report that senile mice given an anti-inflammatory drug had fewer signs of brain inflammation and were better able to learn new tasks, becoming almost as adept as mice half their age. "We tend to think about the aged brain in the same way we think about neurodegeneration: Age involves loss of function and dead cells. But our new data tell a different story about why the aged brain is not functioning well: It is because of this "fog" of inflammatory load. But when you remove that inflammatory fog, within days the aged brain acts like a young brain. It is a really, really optimistic finding, in terms of the capacity for plasticity that exists in the brain. We can reverse brain aging."

The successful treatment in mice supports a radical new view of what causes the confusion and dementia that often accompany aging. More and more research shows that, with age, the filtration system that prevents molecules or infectious organisms in the blood from leaking into the brain - the so-called blood-brain barrier - becomes leaky, letting in chemicals that cause inflammation and a cascade of cell death. After age 70, nearly 60% of adults have leaky blood- brain barriers, according to magnetic resonance imaging (MRI) studies.

An accompanying paper shows that the inflammatory fog induced by a leaky blood-brain barrier alters the mouse brain's normal rhythms, causing microseizure-like events - momentary lapses in the normal rhythm within the hippocampus - that could produce some of the symptoms seen in degenerative brain diseases like Alzheimer's disease. Electroencephalograms (EEGs) revealed similar brain wave disruption, or paroxysmal slow wave events, in humans with epilepsy and with cognitive dysfunction, including Alzheimer's and mild cognitive impairment (MCI).

Scientists have long suspected that a leaky blood-brain barrier causes at least some of the tissue damage after brain injury and some of the mental decline that comes with age. But no one knew how. In 2007, researchers linked these problems to a blood protein, albumin. In 2009, they showed that when albumin leaks into the brain after trauma, it binds to the TGF-β receptor in brain cells called astrocytes. This triggers a cascade of inflammatory responses that damage other brain cells and neural circuits, leading to decreased inhibition and increased excitation of neurons and a propensity toward seizures.

In the new studies, researchers showed that introducing albumin into the brain can, within a week, make the brains of young mice look like those of old mice, in terms of hyperexcitability and their susceptibility to seizures. These albumin-treated mice also navigated a maze as poorly as aged mice. When they genetically engineered mice so that they could knock out the TGF-β receptor in astrocytes after they'd reached old age, the senile mouse brains looked young again. The mice were as resistant to induced seizures as a young mouse, and they learned a maze like a young mouse. Researchers developed a small-molecule drug that blocks the TGF-β receptor in astrocytes only, and that could traverse the blood-brain barrier. When they gave the drug, called IPW, to mice in doses that lowered the receptor activity level to that found in young mice, the brains of the aged mice looked younger, too. They showed young brain-like gene expression, reduced inflammation and improved rhythms - that is, reduced paroxysmal slow wave events - as well as reduced seizure susceptibility. They also navigated a maze or learned a spatial task like a young mouse.

Bitter taste receptors play crucial roles in detecting bitter compounds not only in the oral cavity, but also in other tissues where they are involved in a variety of non-tasting physiological processes. Disorders or modifications in the sensitivity or expression of these receptors can affect physiological functions. Here we evaluated the role of the bitter receptor TAS2R38 in attainment of longevity, since it has been widely associated with individual differences in taste perception, food preferences, diet, nutrition, immune responses and pathophysiological mechanisms.

Our results show that the genetically homogeneous cohort of subjects ranging in age from 90 to 105 years of an area recognised as one of the world's longevity hot spots, differed based on the genotype distribution and haplotype frequencies of TAS2R38 gene from the two genetically heterogeneous cohorts from the South of Sardinia where the longevity level is distinctly lower. Results show in the centenarian cohort an increased frequency of subjects carrying the homozygous genotype for the functional variant of TAS2R38 (PAV/PAV) and a decreased frequency of those having homozygous genotype for the non-functional form (AVI/AVI), as compared to those determined in the two control cohorts.

A number of studies on human nutrition have suggested that the TAS2R38 variants and the related 6-n-propylthioural (PROP) phenotype may influence dietary behaviour and nutritional status. The possible association between PROP responsiveness and perception and intake of fats has been extensively studied, but with controversial results. The widely accepted hypothesis is that PROP non-tasters, compared to PROP super-tasters, show a reduced ability to perceive dietary fat which could lead them to increase the consumption of high-fat foods to compensate the reduced perception. In agreement with this assumption, the high frequency of the tasting homozygous genotype (PAV/PAV) and the low frequency of the non-tasting one (AVI/AVI), that we found in centenarian subjects, suggest that these individuals may have reached an exceptional longevity because of their genetic predisposition to a low-fat diet.

On the other hand, the extreme bitterness intensity of PROP super-tasters has been shown to be the primary reason for avoiding bitter-tasting fruits and vegetables. Since many bitter-tasting compounds in foods (e.g., flavonoids, phenols, glucosinolates) have benefit effects for health, our results in the centenarian cohort seem to be in contrast with the possibility that TAS2R38 genotype is a genetic factor that favour an adequate intake of fruits and vegetables or other bitter foods recommended for a healthy life. However, only a few studies have investigated the relationship between TAS2R38 variants and vegetable intake obtaining controversial results. The notion that TAS2R38 might serve to govern food intake is interesting, but eating behaviour is a complex phenomenon influenced by a broad range of environmental factors.

In addition, it is known that TAS2R38 receptor serves other genotype-dependent roles which are relevant for health, with the PAV form associated with an efficient immune response, a favourable body composition, as well as with physiological processes. On the contrary, the AVI group is associated with a higher risk to develop many dysfunctions and diseases. Therefore, it is not surprising that we find in the centenarian cohort an increased frequency of homozygous subjects for the functional variant of TAS2R38 (PAV) and above all a decreased frequency of those having homozygous genotype for the non-functional form (AVI).

It has been known for some time that certain fat molecules in our bloodstream can trigger an inflammatory response. Patients with higher levels of these fats in their blood have a significantly greater chance of dying early from kidney damage or vascular disease. Now a research team was able to show how these fat molecules interact with body cells and how they can mobilize the body's own immune system to damaging effect.

"Our work has involved studying a special group of lipids, the triglycerides. We've been able to show that when these naturally occurring fats are present at elevated concentrations they can alter our defense cells in such a way that the body reacts as if responding to a bacterial infection. This leads to inflammation, which, if it becomes chronic, can damage the kidneys or cause atherosclerosis - the narrowing of arteries due to a build up of deposits on the inner arterial wall. And atherosclerosis is one of the main causes of heart attacks and strokes."

The large-scale study was able to demonstrate that patients with elevated levels of triglycerides in their blood had a significantly higher mortality rate than comparison groups with a similar health history. Blood triglyceride levels rise substantially in people who eat a high-fat diet. As a result of biochemical changes, the triglycerides develop toxic properties that activate the body's innate immune system via the NLRP3 inflammasome. This initiates a series of self-destructive processes including those in which the walls of the arteries are attacked and the blood vessels become occluded, reducing blood flow.

Do you consider aging to be a disease or, at least, a co-morbid syndrome?

I think you can make an argument that it's a disease, and you can also make an argument that it's a risk factor for disease, but to me, fundamentally, it doesn't matter. It's the biggest driver of chronic diseases, loss of function late in life, and has a huge impact on life quality and health care costs. So we have to do something about aging, whatever you call it, and I don't think it's so important what we call it; it's more important that we all agree that we have to slow down this process.

I think that the regulatory declaration of aging as a disease could certainly have a positive impact, because if aging is a disease, then it's much easier to develop therapies and get reimbursed for therapies, so I'm totally supportive of that effort. I think that, however, we don't call cholesterol a disease, but we treat cholesterol because it's a risk factor, so the FDA does approve interventions on targeted risk factors as well. I think we have to differentiate whether we're discussing this from a conceptual point of view or from a regulatory point of view. Either way, we need the FDA to recognize the fact that aging is driving these other diseases that they care so much about, whether they want to call it a disease or recognize it as a validated risk factor. Either way, something has to happen so that we can develop interventions.

We sometimes hear people say that we don't know enough about aging to do anything about it; however, others argue that we know enough now to start testing interventions and moving forward. Would you agree that we are at the point where we can start doing this?

I'm totally committed to the idea of testing candidate interventions in humans. I think we're totally ready to do that; we have a range of safe interventions that we can test, so we have very low risk of doing harm, and the field will move forward dramatically if we can validate even one or two of these strategies. I believe exercise is more or less already validated, but what I'm talking about are some of the small molecule strategies and other kinds of interventions that are being developed. If we can validate that a couple of those work, I think it'll have a huge positive impact on the field.

Singapore is projected to have a population made up of nearly 50% of senior citizens by 2050; what do you think will be the biggest challenge facing the elder care sector?

I think that we have to change the system. You can't just build hospitals, because there are multiple challenges with that. First of all, you have a lot of sick people on a small island; it's hard to treat all of them. There are not enough doctors and not enough hospitals; there are not enough caregivers to take care of older people. Perhaps most importantly, there are not enough younger workers to keep the economy going to pay for all the costs of the older people. We have to change the paradigm. I don't think there's any solution on Singapore except keeping people healthy longer. We're going to have to raise the retirement age. The people that are working later, they're already doing that, and that's not going to work unless those people are healthy and functional. We think we're trying to provide an essential component of what Singapore and other countries like it need to get through this demographic crisis that's happening in the next 30 or 40 years.

The intestinal tract is colonized by billions of bacteria and other microorganisms that play numerous beneficial roles, but improperly controlled microbiota can lead to chronic inflammatory diseases. Previous studies have shown the intestinal microbiota are associated with inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, and diseases characterized by low-grade inflammation of the intestinal tract, such as obesity and metabolic syndrome.

Therapeutic options have focused on lessening the inflammatory response and have often overlooked the contribution of the intestinal microbiota. The researchers wanted to determine if a targeted immune response could be used to beneficially shape the intestinal microbiota and protect against inflammatory diseases. Previously, they found that a common feature of microbiotas associated with inflammation is an increased level of expression of flagellin by select microbiota members, a protein that forms the appendage that enables bacterial mobility, which can drive bacteria to penetrate the intestinal mucosa and disrupt homeostasis.

The researchers immunized mice with flagellin to elicit an adaptative immune response and demonstrated targeted immunization against bacterial flagellin is sufficient to beneficially alter the composition and function of the intestinal microbiota. Anti-flagellin antibodies were produced and affected the microbiota by reducing its pro-inflammatory potential and ability to penetrate its host. These alterations were associated with protection against chronic inflammatory diseases.

Despite its prevalence, there remains no available pharmacological therapies to treat hearing loss. Loss of hair cells (HCs), the inner ear sensory cells that detect sound and sense balance, is a major cause of hearing loss and vestibular dysfunction in humans. In lower vertebrates such as birds, fish, and amphibians, HC loss triggers supporting cells (SCs) to re-enter the cell cycle. Proliferating SCs then transdifferentiate into new HCs, resulting in the recovery of hearing and vestibular functions. In contrast, the mature mammalian cochlea completely lacks the capacity to spontaneously proliferate or regenerate HCs, and has very limited regeneration potential in the vestibular system.

In the young mammalian inner ear, SC-to-HC transdifferentiation can be induced by overexpression of HC fate-determining transcription factor, Atoh1. An early study provided evidence that Atoh1 overexpression had limited but similar effects in the adult mammalian cochlea, however, subsequent studies failed to reproduce the essential findings. It is therefore suggested that, in the adult inner ear, overexpression of Atoh1 in SCs alone is inefficient in promoting HC regeneration. To recapture the capacity to respond to HC induction signals, it is likely that mature SCs need to first regain the properties of their younger biological selves.

To identify potential reprogramming factors in the adult mammalian inner ear, we began by studying chick and zebrafish HC regeneration models and uncovered that reactivation of Myc is a major event that leads to cell cycle re-entry. Additional studies have shown that overexpression of Notch1, a receptor important in mammalian inner ear early development and patterning, is sufficient to induce formation of the prosensory domain of the developing mouse otocyst. We hypothesize that the combined action of MYC and NOTCH1 may be sufficient to reprogram adult mouse inner ear cells for cell cycle re-entry and the reprogrammed SCs may regain the properties enabling them to transdifferentiate into HCs in the presence of induction signals.

In this study, by adenovirus-mediated delivery and inducible transgenic mouse models, we demonstrate the proliferation of both HCs and SCs by combined Notch1 and Myc activation in in vitro and in vivo inner ear adult mouse models. These proliferating mature SCs and HCs maintain their respective identities. Moreover, when presented with HC induction signals, reprogrammed adult SCs transdifferentiate into HC-like cells both in vitro and in vivo. Finally, our data suggest that regenerated HC-like cells likely possess functional transduction channels and are able to form connections with adult auditory neurons.

Epigenetic processes, among which DNA methylation is one of the most well studied, are fundamental in human aging. Studies on DNA methylation have identified age-associated changes in methylation levels shared by individuals, and have also reported an increasing divergence of methylation levels between individuals with age. While the role of DNA methylation in aging has been widely studied, epigenetic mutations, here defined as aberrant methylation levels compared to the distribution in a population, are less understood.

Epigenetic mutations may be involved in cancer development and important for human aging. Unlike age-associated changes in methylation levels that are shared among individuals, the incidences of epigenetic mutations are rare, stochastic, and inconsistent between individuals. Recently, emerging studies on methylation variability have also identified differentially varied CpG sites associated with cancer field defects. Epigenetic mutations can partly explain the increasing variability of methylation levels between individuals over time, but conversely, highly varied methylation sites do not necessarily contain extreme outliers. The extreme methylation levels may concur stronger biological consequences, such as cancer.

However, the study on epigenetic mutations and aging was based on a cross-sectional study, it needs to be validated in a longitudinal setting, where the accumulation of epigenetic mutations over time can be followed within the same individuals. It is not yet known what the clinical consequences of accumulated epigenetic mutations are, and if individuals with a high burden of epigenetic mutations are prone to develop cancer as previously suggested.

In this study, we analyzed age-related accumulation of epigenetic mutations from a longitudinal perspective in old Swedish twins, using 994 blood samples collected at up to five time points from 375 individuals in old ages. Apart from being exponentially associated with age, epigenetic mutations were also associated with sex, CD19+ B cell count, genetic background, cancer incidence, and technical factors. We showed once mutations are established, they are stable over time. Furthermore, epigenetic mutations are enriched in important regulatory sites, e.g., promoter regions of genes involved in histone modification processes, which could potentially be an explanation to why people who develop cancer have more epigenetic mutations than others do.

We further classified epigenetic mutations into High/Low Methylation Outliers (HMO/LMO) according to their changes in methylation. We also found that biological factors, including B cell compositions and genetic factors, were more strongly associated with frequent HMOs than LMOs, while frequent LMOs were more influenced by technical factors. Moreover, cancer diagnosis was significantly associated with the increase of epigenetic mutations, especially among frequent HMOs, while the same was not true for LMOs. Furthermore, we concluded that the age-related accumulation of epigenetic mutations was not related to genetic factors, hence is driven by stochastic or environmental effects.

Calorie restriction (CR) has been shown to be an established life-extension method regulating age-related diseases as well as aging itself. Although different in methodology (usually 20%-40% less than ad libitum intake, a 40% reduction in most cases), CR showed a prolonged lifespan in a wide range of species from yeast to non-human primates, and supports healthy human aging. Furthermore, CR exerts preventive effects on various age-related conditions such as cancer, neurodegenerative diseases, cardiovascular, and other metabolic diseases. The diverse efficacy of CR in counteracting aging and age-related diseases has made it the golden standard of aging intervention studies.

Although the anti-aging effects of CR are reproducible, the exact mechanisms of how CR exerts its anti-aging effects are debatable, because CR regulates several different aspects of physiology. These changes include modifications in the energy-sensing signaling, oxidative stress, inflammation, and other intercellular and intracellular processes. Among the many changes induced by CR, energy production and utilization is the most directly regulated signaling exerted by CR. Since reduced energy intake and changes in nutritional status following CR may change the molecular signaling pathways associated with energy-sensing mechanisms, other mechanisms may be secondary effects to this process.

Based on the induction mechanism of autophagy and its role during starvation, it was predicted that CR might induce the autophagic process. Indeed, under many different settings of nutrient deprivation conditions, including in CR, autophagy is induced to regulate the organism's homeostasis. Although it is clear that CR represents a strong physiologically autophagic inducer, it is uncertain whether autophagy contributes to the anti-aging effects of CR. Recently, several studies have shown that autophagy induction was essential for the anti-aging effects of CR. CR was shown to promote longevity or protect from hypoxia through a Sirtuin-1-dependent autophagy induction process. Another study also showed that life extension through methionine restriction depended upon autophagy activation. Growing evidence supports the notion that autophagy has a substantial role in the beneficial effects of CR. In addition to research on longevity, other studies have shown that CR robustly induces autophagy under various physiological and pathological conditions, and that it has a protective effect in the maintenance of normal functions in the organism.

Mitochondrial functions and telomere functions have mostly been studied independently. In recent years, it, however, has become clear that there are intimate links between mitochondria, telomeres, and telomerase subunits. Mitochondrial dysfunctions cause telomere attrition, while telomere damage leads to reprogramming of mitochondrial biosynthesis and mitochondrial dysfunctions, which has important implications in aging and diseases. In addition, evidence has accumulated that telomere-independent functions of telomerase also exist and that the protein component of telomerase TERT shuttles between the nucleus and mitochondria under oxidative stress.

Our previously published data show that the RNA component of telomerase TERC is also imported into mitochondria, processed, and exported back to the cytosol. Mitochondrial localization of TERT is a cell type-specific event that protects the cells from oxidative stress. What is the exact function of mitochondrion-localized TERT within the mitochondrial matrix, however, remains to be elucidated. This data shows a complex regulation network where telomeres, nuclear genome, and mitochondria are co-regulated by multi-localization and multi-function proteins and RNAs.

Researchers have found that the body naturally floods the area around a new bone injury with the pro-healing adenosine molecules, but those locally high levels are quickly metabolized and don't last long. They wondered if maintaining those high levels for longer would help the healing process. But there was a catch. "Adenosine is ubiquitous throughout the body in low levels and performs many important functions that have nothing to do with bone healing. To avoid unwanted side effects, we had to find a way to keep the adenosine localized to the damaged tissue and at appropriate levels."

The solution was to let the body dictate the levels of adenosine while helping the biochemical stick around the injury a little bit longer. The researchers designed a biomaterial bandage applied directly to the broken bone that contains boronate molecules that grab onto the adenosine. However, the bonds between the molecules do not last forever, which allows a slow release of adenosine from the bandage without accumulating elsewhere in the body. Researchers first demonstrated that porous biomaterials incorporated with boronates were capable of capturing the local surge of adenosine following an injury. The researchers then applied bandages primed to capture the host's own adenosine or bandages preloaded with adenosine to tibia fractures in mice. After more than a week, the mice treated with both types of bandages were healing faster than those with bandages not primed to capture adenosine. After three weeks, while all mice in the study showed healing, those treated with either kind of adenosine-laced bandage showed better bone formation, higher bone volume, and better vascularization.

The results showed that not only do the adenosine-trapping bandages promote healing, they work whether they're trapping native adenosine or are artificially loaded with it, which has important implications in treating bone fractures associated with aging and osteoporosis. "Our previous work has shown that patients with osteoporosis don't produce adenosine when their bones break. These early results indicate that these bandages could help deliver the needed adenosine to repair their injuries while avoiding potential side effects."