Turn.bio is Gary Hudson's latest company, now that others are running the day to day development at Oisin Biotechnologies. The Turn.bio staff are working on a particular take on the idea of inducing pluripotence in cells in vivo as a form of compensatory therapy for aging. This is a concept that struck me as being fairly crazy the first time I saw it discussed in a research publication. It is certainly possible to reliably reprogram somatic cells of near any sort into what are known as induced pluripotent stem cells, capable of differentiating into any type of cell. This is the foundation for the production of arbitrary cell types for transplantation. But doing it inside a living animal? Surely a recipe for cancer and more cancer, as the pluripotent cells replicate uncontrollably outside the normal restraints of a structured tissue.

Oddly, however, the initial outcome in mice was not cancer and more cancer. It was a set of benefits to health and tissue function that looked a lot like the results of stem cell therapies, most likely achieved via the signaling produced by the newly induced pluripotent stem cells. It remains to be seen what the risks look like over the long term, but the result prompted some interest and following studies in the research community. Given this, what if it were possible to guide cells only part-way into a pluripotent state, and only temporarily, generating beneficial signals for a time without any meaningful risk of pluripotent cells floating around in tissues for the long term? That is what the Turn.bio staff are working on. The result may be a more controllable, guided way to achieve the benefits of stem cell therapy without the stem cells. The paper here is the basis for their current development program.

Transient non-integrative nuclear reprogramming promotes multifaceted reversal of aging in human cells

The process of nuclear reprogramming to induced pluripotent Stem cells (iPSCs) is characterized, upon completion, by the resetting of the epigenetic landscape of cells of origin, resulting in reversion of both cellular identity and age to an embryonic-like state. Notably, if the expression of the reprogramming factors is applied only for a short time and then stopped - before the so-called Point of No Return (PNR) - the cells return to the initiating somatic cell state. These observations suggest that if applied for a short enough time (transient reprogramming), the expression of reprogramming factors fails to erase the epigenetic signature defining cell identity; however, it remains unclear whether any substantial and measurable reprogramming of cellular age can be achieved before the PNR and if this can result in any amelioration of cellular function and physiology. To test this, we first evaluated the effect of transient reprogramming on the transcriptome of two distinct cell types - fibroblasts and endothelial cells - from aged human subjects, and we compared it with the transcriptome of the same cell types isolated from young donors.

We utilized a non-integrative reprogramming protocol that we optimized, based on a cocktail of mRNAs expressing OCT4, SOX2, KLF4, c-MYC, LIN28 and NANOG (OSKMLN). Our protocol consistently produces induced pluripotent stem cell (iPSC) colonies, regardless of age of the donors, after 12-15 daily transfections; we reasoned that the PNR in our platform occurs at about day 5 of reprogramming, based on the observation that the first detectable expression of endogenous pluripotency-associated lncRNAs occurs at day 5. Therefore, we adopted a transient reprogramming protocol where OSKMLN were daily transfected for four consecutive days, and performed gene expression analysis two days after the interruption.

Analysis of transcriptomic signatures revealed that transient reprogramming triggers a more youthful gene expression profile, while retaining cell identity. Epigenetic clocks based on DNA methylation levels are the most accurate molecular biomarkers of age across tissues and cell types and are predictive of a host of age-related conditions including lifespan. Exogenous expression of canonical reprogramming factors (OSKM) is known to revert the epigenetic age of primary cells to a prenatal state. To test whether transient expression of OSKMLN could reverse the epigenetic clock, we used two epigenetic clocks that apply to human fibroblasts and endothelial cells: Horvath's original pan-tissue epigenetic clock, and the more recent skin and blood clock. According to the pan-tissue epigenetic clock, transient OSKMLN significantly reverted the DNA methylation age.

This data demonstrates that transient expression of OSKMLN can induce a rapid, persistent reversal of cellular age in human cells at the transcriptomic, epigenetic, and cellular levels . Importantly, these data demonstrate that the process of "cellular rejuvenation" - that we name Epigenetic Reprogramming of Aging, or "ERA" - is engaged very early and rapidly in the iPSC reprogramming process. These epigenetic and transcriptional changes occur before any epigenetic reprogramming of cellular identity takes place, a novel finding in the field.

Sarcopenia is an age-related condition that is characterized by loss of muscle mass and force production. We wanted to test whether transient reprogramming of aged muscle stem cells (MuSCs) would improve a cell-based treatment in restoring physiological functions of muscle of older mice. To test this, we first performed electrophysiology to measure tetanic force production in tibialis anterior (TA) muscles isolated from young (4 months) or aged (27 months) immunocompromised mice. We found that TA muscles from aged mice have lower tetanic forces compared to young mice, suggesting an age-related loss of force production. Next, we isolated MuSCs from aged mice (20-24 months). After treating aged MuSCs, we transplanted them into injured TA muscles of aged (27 months) immunocompromised mice. We waited 30 days to give enough time to the transplanted muscles to fully regenerate. We then performed electrophysiology to measure tetanic force production.

Muscles transplanted with untreated aged MuSCs showed forces comparable to untransplanted muscles from aged control mice. Conversely, muscles that received treated aged MuSCs showed tetanic forces comparable to untransplanted muscles from young control mice. These results suggest that transient reprogramming in combination with MuSC-based therapy can restore physiological function of aged muscles to that of youthful muscles.

Periodontitis is the later stage of gum disease, an inflammatory condition largely caused by particular strains of bacteria found in the mouth. While there is a fair amount of promising work related to destroying or sabotaging the disease-causing mechanisms of those bacterial species, nothing has yet made the leap to earnest clinical development. It is thought, based on epidemiological data showing an association with mortality, and on a reasonable examination of the mechanisms involved, that periodontitis can spread inflammatory signaling elsewhere in the body, particularly to the heart and the brain, and thereby accelerate the progession of age-related conditions. The research here, however, using study data for a large number of patients, shows only a modest effect on the incidence of dementia due to the presence of periodontitis.

Gum disease (gingivitis) that goes untreated can become periodontitis. When this happens, the infection that affected your gums causes loss in the bone that supports your teeth. Periodontitis is the main cause of tooth loss in adults. Interestingly, periodontitis is also a risk factor for developing dementia, one of the leading causes for disability in older adults. Recently, researchers in South Korea studied the connection between chronic periodontitis and dementia. The research team examined information from the National Health Insurance Service-Health Screening Cohort (NHIS-HEALS). In South Korea, the NHIS provides mandatory health insurance covering nearly all forms of health care for all Korean citizens. The agency also provides health screening examinations twice a year for all enrollees aged 40 years or older and maintains detailed health records for all enrollees.

The researchers looked at health information from 262,349 people aged 50 or older. All of the participants were grouped either as being healthy (meaning they had no chronic periodontitis) or as having been diagnosed with chronic periodontitis. The researchers followed the participants from January 1, 2005 until they were diagnosed with dementia, died, or until the end of December 2015, whichever came first. The researchers learned that people with chronic periodontitis had a 6 percent higher risk for dementia than did people without periodontitis. This connection was true despite behaviors such as smoking, consuming alcohol, and remaining physically active.

Link: https://www.healthinaging.org/blog/periodontitis-may-raise-the-risk-for-developing-dementia/

The Academy for Health and Lifespan Research was recently announced, an initiative analogous to that of the long-running Longevity Dividend group, but hopefully more energetic and more focused on at least some rejuvenation biotechnologies such as senolytic therapies. The principals include many of the researchers now involved in startup biotech companies working on ways to intervene in the mechanisms of aging, and the goal is to generate greater support for development of means to slow or reverse aging and age-related disease. David Sinclair is associated with Life Biosciences and its collection of portfolio companies, and here discusses the Academy and its future role.

Tell me about the academy. Is it intended to be mainly an advocacy organization?

The academy has been formed because our field of aging and longevity research has reached a point of maturity where the leaders in the field believe that we can have - or will have - a big impact on the planet. That impact will be in medicine, in health span, and in its knock-on effect on everything from human productivity to Social Security. We wanted to come together to speak with one voice, to be able to help corporations and governments understand what things they should be thinking about now and give realistic projections of what life is going to be like 10, 20, 50 years from now. Because it's not a question of if there's going to be an impact, it's really a question of what kind of a future we want to build when this happens.

What kind of impact are we talking about? When you think about 10, 20, 50 years in the future, how do you see aging being transformed in the U.S. and around the world?

By impact, I mean that instead of tackling one disease at a time, which is the way 20th-century medicine and pharmaceutical development was practiced, we believe we can develop medicines that will treat aging at its source and thereby have a much greater impact on health and lifespan than drugs that target a single disease. Heart disease medicine may keep your heart healthy for an extra five or 10 years, but does nothing for your brain. So, we're ending up with a population of people who live longer but not better and who need a lot of help, if they're not completely in the grip of dementia. We don't think that's necessarily the only or the best approach.

Now, we have the knowledge. We're developing the technologies to not just delay these diseases of aging but actually reverse aspects of them. Imagine you have a treatment for heart disease, but as a side effect you'd also be protected against Alzheimer's, cancer, and frailty. You'd live a longer and healthier life. The reason we can extend the lifespan of animals is not because we can just make them live longer, but we keep them healthy. The animals don't get heart disease, cancer, Alzheimer's, until sometimes 20 percent later in their life. And so that's 20 percent longer youth, not just 20 percent longer life.

Are there regulatory hurdles? When we've spoken in the past, you've mentioned that the FDA considers aging a natural process and therefore won't approve drugs to treat it.

Opinions are changing rapidly about whether aging should be a condition that a doctor can prescribe a medicine for. We currently live in a world where aging is so common that it's considered by most of the world, including the medical community, as something that's natural and inevitable. And if something's considered inevitable, typically you don't focus on it in the same way as something you can treat. Cancer was a natural part of life at one time, in the same way that aging is today. A hundred years ago, doctors didn't focus on treating cancer as much as we do now, because then you couldn't do much, if anything, about it.

There are now dozens of companies working on therapies that could potentially extend overall human health and lifespan, but none of them are working specifically toward an approval for aging because the FDA wouldn't even know where to start. But that may be changing quickly. I've been part of a group that talked with the FDA, and they are willing and also quite enthusiastic about considering a change that defines aging as a disease. They would like us, first, to show that it's possible to change the rate of aging, which in my view is backward, but that's what they want. In Australia, the government is 100 percent behind this, at the FDA level and in the Ministry for Health. I'm hopeful that one country in the world - it may be Australia, it may be the U.S., it may be an Asian country - will change its definition of aging. Once one country changes its definition, then it will be a domino effect and the others will follow.

Link: https://news.harvard.edu/gazette/story/2019/03/anti-aging-research-prime-time-for-an-impact-on-the-globe/

Raised blood pressure with age, hypertension, is a major downstream consequence of low-level biochemical damage and cellular dysfunction, converting it into high-level structural damage in the body and brain. Hypertension is an important proximate contributing cause of ultimately fatal age-related conditions of the cardiovascular system, kidneys, brain, and lungs, among others. Pressure damage in delicate tissues degrades function in many organs, particularly in the central nervous system where there is little to no regeneration capable of reversing that damage. More subtly, hypertension also causes heart muscles to enlarge and weaken, contributing to heart failure. Hypertension also accelerates the development of atherosclerosis, through mechanisms independent of other factors such as chronic inflammation.

Hypertension is so great a contribution to age-related disease, such an important mediating mechanism, that it is possible to produce sizable reductions in mortality by forcing a lower blood pressure, even without addressing the underlying causes in any way. The widespread use of antihypertensive medications to achieve this goal is one of the success stories of mainstream medicine in recent decades. There are, sadly, not all that many mechanisms that rise to this level of importance as single downstream consequences of low-level biochemical damage in aging. Chronic inflammation is another, but beyond that the only way to make significant progress towards control of aging is to repair the underlying damage. Attempting to address downstream consequences is largely very hard and of limited utility. Control of blood pressure and inflammation are outliers in this context.

Sustained blood pressure control and coronary heart disease, stroke, heart failure, and mortality: An observational analysis of ALLHAT

Treatment and control of high blood pressure (BP) is a key strategy for reducing coronary heart disease (CHD), stroke, heart failure (HF), and all-cause mortality among adults with hypertension. Accordingly, clinical practice guidelines provide recommendations for accurately identifying adults with hypertension, initiating appropriate antihypertensive therapy, and achieving predefined BP goals that have been shown to be associated with lower cardiovascular disease (CVD) and all-cause mortality event rates in randomized trials. However, less is known about the role of sustaining BP control over time.

In clinical practice, patients may be followed over many years and often experience times of controlled as well as uncontrolled BP. There are several reasons why BP control may change over time, including changes in patients' health status or medication adherence, variability in BP measurement from visit to visit, or reduction in antihypertensive medication intensity due to concerns about overtreatment on the part of the provider. The proportion of visits at which patients achieve BP control can easily be calculated, could be used to facilitate discussions with patients about treatments goals, and could be used as a performance measure for quality improvement. Also, data on the effects of maintaining sustained BP control could be used to support greater treatment consistency over time or conversely, to allow higher BP levels at some visits.

Findings from a limited number of studies suggest that having BP control at a greater proportion of visits over time is associated with a lower CVD risk. However, prior studies included primarily white participants, those with existing coronary heart disease (CHD), or with multiple CVD risk factors. The purpose of the current study was to determine the association of sustained BP control with CHD, stroke, HF, and mortality in an observational analysis of a demographically and clinically diverse population within a large clinical trial, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Participation was restricted to 24,309 participants with four to seven visits with systolic BP (SBP) measurements during a 22-month period. Participants were as having sustained BP control (SBP lower than 140 mm Hg) at 100%, 75% to 100%, 50% to 75%, and fewer than 50% of visits during this period.

In this observational analysis of participants from ALLHAT, those with SBP control, defined as SBP lower than 140 mm Hg at fewer than 50% of study visits, were more likely to have a stroke, develop HF, or experience the combined outcome of fatal CHD/nonfatal myocardial infarction, stroke, or HF. These associations were present after adjustment for potential confounders. Compared to those with SBP control at 100% visits, adjusted hazard rations among those with SBP control at fewer than 50% of visits was 1.16 for fatal CHD/nonfatal myocardial infarction, 1.71 for stroke, 1.63 for heart failure, 1.39 for the composite CVD outcome, and 1.14 for mortality. Sustained SBP control may be beneficial for preventing stroke, heart failure, and CVD outcomes in adults taking antihypertensive medication.

The story of the past few decades has been a steady reduction in the incidence and mortality of the major age-related diseases that dominated old age in the last century. This has been a strange triumph, in the sense that it was achieved using very inefficient strategies for medical research and development, coupled with an aggressive push towards prevention through lifestyle choice. At no point were the causes of aging deliberately targeted; instead medical efforts focused on tinkering with the downstream consequences of the late disease state. That this combination nonetheless achieved the results that it did is a testament to the dedication of researchers and clinicians. Imagine how much could be achieved given a better research and development strategy, one capable of producing rejuvenation via repair of the causes of aging.

Heart attack prevention and outcomes have dramatically improved for American adults in the past two decades. Compared to the mid-1990s, Americans today are less likely to have heart attacks and also less likely to die from them. Tracking more than four million Medicare patients between 1995 and 2014, this is the largest and most comprehensive study of heart attacks in the United States to date. Its two key findings are that hospitalizations for heart attacks have declined by 38%, and the 30-day mortality rate for heart attacks is at an all-time low of 12%, down by more than a third since 1995.

The researchers believe these gains are no accident. The last 20 years have been marked by national efforts to prevent heart attacks and improve care for those who suffer them. The Centers for Medicare and Medicaid Services, the American College of Cardiology, and the American Heart Association - along with other organizations and "legions of researchers and clinicians and public health experts" - have focused on reducing risk by promoting healthy lifestyles, addressing risk factors, and improving the quality of care.

While the study tallies the impressive overall gains, it also sheds light on the health outcome disparities in America on a county by county basis. "Priority health areas," which were previously identified as lagging areas, saw little or no change in their 30-day mortality rates following heart attack in the past two decades - indicating that they should receive particular attention in future healthcare improvement activities. "We are now at historic lows in the rates of heart attacks and deaths associated with heart attacks. However, this is no time to be complacent. We document extraordinary gains - but the effort is far from finished. The goal is to one day relegate heart attacks to the history of medicine."

Link: https://news.yale.edu/2019/03/15/1990s-heart-attacks-have-become-less-deadly-frequent-americans

Retinal degeneration causes blindness by destroying the photoreceptor cells in the retina. Some forms of degenerative blindness leave intact other cell populations, however. What if those populations could be granted some of the same mechanisms used by photoreceptor cells to pass signals to the optic nerve? Researchers here demonstrate a gene therapy that does just this, a most interesting feat of engineering. It is still a poor alternative to prevention of the condition, or restoration of lost photoreceptor cells, but it is no less impressive for it. This is truly an age of biotechnology.

Scientists inserted a gene for a green-light receptor into the eyes of blind mice and, a month later, they were navigating around obstacles as easily as mice with no vision problems. They were able to see motion, brightness changes over a thousandfold range and fine detail on an iPad sufficient to distinguish letters. The researchers say that, within as little as three years, the gene therapy - delivered via an inactivated virus - could be tried in humans who've lost sight because of retinal degeneration, ideally giving them enough vision to move around and potentially restoring their ability to read or watch video.

Correcting the genetic defect responsible for retinal degeneration is not straightforward, because there are more than 250 different genetic mutations responsible for retinitis pigmentosa alone. About 90 percent of these kill the retina's photoreceptor cells - the rods, sensitive to dim light, and the cones, for daylight color perception. But retinal degeneration typically spares other layers of retinal cells, including the bipolar and the retinal ganglion cells, which can remain healthy, though insensitive to light, for decades after people become totally blind. In their trials in mice, the team succeeded in making 90 percent of ganglion cells light sensitive.

To reverse blindness in these mice, the researchers designed a virus targeted to retinal ganglion cells and loaded it with the gene for a light-sensitive receptor, the green (medium-wavelength) cone opsin. Normally, this opsin is expressed only by cone photoreceptor cells and makes them sensitive to green-yellow light. When injected into the eye, the virus carried the gene into ganglion cells, which normally are insensitive to light, and made them light-sensitive and able to send signals to the brain that were interpreted as sight.

Link: https://news.berkeley.edu/2019/03/15/with-single-gene-insertion-blind-mice-regain-sight/

Given the present wave of investment into the treatment of aging, in both the business and research communities, and given the significant valuations put on the first companies working on senolytic drugs to clear senescent cells, it should come as no surprise to see a land rush underway in the investigation of the biochemistry of cellular senescence. The state of funding for any specific field of research is to a sizable degree steered by what is going on in the world of startups and venture capital. When finding a new mechanism is a potential ticket to valuable intellectual property, a startup company, and production of clinical therapies, then there will be more funding available for researchers involved in the search for mechanisms, and more researchers joining in.

Senescent cells are clearly significant in all aspects of aging, and removing them is proving, in mice at least, to produce robust reversal of aging and age-related disease. Senescent cells, while small in number even in old individuals, produce a potent mix of signals known as the senescence-associated secretory phenotype, or SASP. This SASP generates chronic inflammation, changes the behavior of normal cells for the worse, destructively remodels the extracellular matrix, and more. In some ways it might be considered an actively maintained aspect of aging. Removing senescent cells removes this signaling, and restores tissue function as a result. Other researchers are interested in modulating or suppressing the SASP, but I have to think that this is a much more challenging proposition, given the complexity of SASP signaling.

The open access paper here is an illustrative example of the sort of detailed investigation of the mechanisms of cellular senescence that is taking place today. Some will give rise to efforts to develop new therapies to destroy, prevent, or alter the behavior of senescent cells. This sort of work is spreading and well funded to a degree that would have been unimaginable prior to the noted 2011 demonstration of the relevance of senescent cells to aging. All of this is driven by success in showing that removal of senescent cells reverses aging and age-related disease, and by the significant investment in clinical development that followed.

The p53/miRNAs/Ccna2 pathway serves as a novel regulator of cellular senescence: Complement of the canonical p53/p21 pathway

It is demonstrated that the presence and progressive accumulation of senescent cells contribute to overall organism aging; senescent cells aggregate in aging tissues have been considered as a causal factor for aging-related disorders. Senescent cells are characterized as irreversible growth arrest, increased senescence-associated β-galactosidase activity, and undergo distinctive phenotypic alterations, including profound chromatin and secretome changes. Research over last three decades has uncovered a variety of signaling pathways that are involved in the regulation of cellular senescence and determine the lifespan in a manner conserved across species, including insulin growth factor 1 (IGF-1) signaling (IIS), rapamycin (mTOR) signaling, and the sirtuin family. Additionally, p53 activation exerts critical roles in modulating cellular senescence and organismal aging. Senescence-induction stressors including DNA lesions, telomere shortening, oxidative stress, and oncogene activation, initially halt cell cycle progression through p53-mediated induction of p21 and finally trigger cellular senescence.

MicroRNAs (miRNAs) are conserved tiny noncoding RNAs generated from endogenous hairpin-shaped precursors, which have emerged as novel and fundamental actors in gene regulation. These small RNA molecules can direct bind to specific sites presented in target messenger RNA (mRNA). As the recognition of target mRNAs mainly depends on the seed region of the mature miRNA, one single miRNA might regulate hundreds of target mRNAs; meanwhile, distinct miRNAs might co-regulated the same mRNA, thus orchestrating a large variety of physiological and cellular processes. Recently, a growing body of evidence has suggested the potential role of miRNAs in modulating the aging process and cellular senescence. In this work, we evaluated the miRNA and mRNA profile in the physiological aging 20-month-old mouse model by high-throughput analysis.

The data showed that various p53 responsive miRNAs, including miR-124, miR-34a and miR-29a/b/c, were up-regulated in the aging mouse compared to the young mouse. Further investigation unraveled that, similarly to miR-34a and miR-29, miR-124 significantly promoted cellular senescence. As expected, mRNA microarray and gene co-expression network analysis unveiled that the most down-regulated mRNAs were enriched in the regulatory pathways of cell proliferation. Fascinatingly, among these down-regulated mRNAs, Ccna2 stood out as a common target of several p53 responsive miRNAs (miR-124 and miR-29), which functioned as the antagonist of p21 in cell cycle regulation.

Silencing of Ccna2 remarkably triggered the cellular senescence, while Ccna2 overexpression delayed cellular senescence and significantly reversed the senescence-induction effect of miR-124 and miR-29. Moreover, these p53 responsive miRNAs were significantly up-regulated during the senescence process of p21-deficient cells; overexpression of p53 responsive miRNAs or knockdown of Ccna2 evidently accelerated the cellular senescence in the absence of p21. Taken together, our data suggested that the p53/miRNAs/Ccna2 pathway might serve as a novel senescence modulator independent of p53/p21 pathway.

Determinations of biological age based on ever more detailed measurements of human cellular biochemistry are known as clocks. Biological age is distinct from chronological age, as different people age at somewhat different rates. Aging is an accumulation of cell and tissue damage and the consequences of that damage; more damage means a higher biological age. The best known clock examples are the well known varieties of epigenetic clock, based on patterns of DNA methylation that decorate the genome. In recent years, researchers have been rapidly developing other sorts of clock, using other measures of cellular biochemistry and metabolism. The one here is an example of the type, focused on immune system function.

The immune system is the critical function in the body for managing health. It is a complex system with hundreds of different cell-types. Until now, no metric had existed to quantify an individual's immune status. New data, while requiring further development, describes a metric (called IMM-AGE) by which we can accurately understand a person's immune status, providing increased information for accurate prediction and management of risks for disease and death.

This new capability will have drug development implications: Given the importance of immune status in vaccine response, this new data could play a significant role in both the design of future vaccine trials and in re-evaluating past vaccine trials. Moreover, this new metric for immune aging could see chronological age augmented by "immune age" as a way of improving drug development programs - providing for enhanced clinical trial entry/exclusion criteria that can elicit a more homogenous response and greater likelihood of success.

The researchers developed their unique data by following a group of 135 healthy volunteers for nine years, taking annual blood samples which were profiled against a range of 'omics' technologies (cell subset phenotyping, functional responses of cells to cytokine stimulations and whole blood gene expression). This captured population- and individual-level changes to the immune system over time, which when analyzed using a range of novel, immune aligned, machine learning analytical technologies, enabled identification of patterns of cell-subset changes, common to those in the study, despite the large amount of variation in their immune system states. The data and metrics generated was then validated against a cohort of more than 2,000 patients from the Framingham Heart Study.

Link: https://www.eurekalert.org/pub_releases/2019-03/c-ndu031119.php

Researchers here present an interesting view of the variance in the burden of age-related disease exhibited by populations around the world. Unsurprisingly, the impact of age falls most heavily on those living in the poorest and least developed regions. Modern medicine and the other comforts of technology, for all that they do not directly target the causes of aging, do manage to have a sizable influence on the pace at which aging and age-related disease progresses over a lifetime. The largest gaps are mostly likely due to a combination of sanitation, particulate exposure from fires, and control of pathogens - akin to the difference between today and the 19th century. But the underlying reasons for the differences between wealthier nations, such as Japan versus countries of Western Europe, tend to be harder to pin down.

A 30-year gap separates countries with the highest and lowest ages at which people experience the health problems of a 65-year-old. Researchers found 76-year-olds in Japan and 46-year-olds in Papua New Guinea have the same level of age-related health problems as an "average" person aged 65. These negative effects include impaired functions and loss of physical, mental, and cognitive abilities resulting from the 92 conditions analyzed, five of which are communicable and 81 non-communicable, along with six injuries.

The study is the first of its kin. Where traditional metrics of aging examine increased longevity, this study explores both chronological age and the pace at which aging contributes to health deterioration. The study uses estimates from the Global Burden of Disease study (GBD). Researchers measured "age-related disease burden" by aggregating all disability-adjusted life years (DALYs), a measurement of loss of healthy life, related to the 92 diseases. The findings cover 1990 to 2017 in 195 countries and territories. For example, in 2017, people in Papua New Guinea had the world's highest rate of age-related health problems with more than 500 DALYs per 1,000 adults, four times that of people in Switzerland with just over 100 DALYs per 1,000 adults. The rate in the United States was 161.5 DALYs per 1,000, giving it a ranking of 53rd, between Algeria at 52nd with 161.0 DALYs per 1,000 and Iran at 54th with 164.8 DALYs per 1,000.

Using global average 65-year-olds as a reference group, researchers also estimated the ages at which the population in each country experienced the same related burden rate. They found wide variation in how well or poorly people age. Ranked first, Japanese 76-year-olds experience the same aging burden as 46-year-olds in Papua New Guinea, which ranked last across 195 countries and territories. At 68.5 years, the United States ranked 54th, between Iran (69.0 years) and Antigua and Barbuda (68.4 years).

Link: http://www.healthdata.org/news-release/what-age-do-you-feel-65

SGLT-2 inhibitors, or gliflozins, are a newer and still expensive class of anti-diabetic drug. They work by interfering in the trafficking of glucose, preventing the kidney from reclaiming glucose and introducing it back into the bloodstream. The glucose is instead excreted. Analogously to metformin, another anti-diabetic drug, it is proposed that inhibition of SGLT-2 in some ways mimic the effects of calorie restriction, triggering beneficial cellular housekeeping mechanisms that usually only turn on during periods of fasting or low calorie intake. Size of effect and degree of side-effects are always the questions in these matters, however. One should hold back any nascent enthusiasm until able to find reliable answers in the literature.

Evidently, a faction of the research community thinks that metformin has a large enough effect size to run a human trial versus aging, in order to push the FDA into accepting aging as an indication. Following that same line of thinking, these researchers would probably also consider this strategy for one or more SGLT-2 inhibitors. That said, one of the points of using metformin as the lever, to try to make the FDA reconsider aging as a medical condition that can be treated, is that metformin is very widely used and has a long history of use. Not that it is particularly effective in the grand scheme of things. It is hard for the FDA to object to it on any grounds other than aging not being a formally defined and approved medical condition that people are permitted to treat, which is exactly the battle that researchers wish to take place.

SGLT-2 inhibitors induce a fasting state that triggers metabolic benefits

SGLT-2 inhibitors are a relatively new class of diabetes drugs that have shown many benefits for people with type 2 diabetes who have not responded well to previous interventions. Researchers set out to understand how these benefits happen. They found that SGLT-2 inhibitors induce a fasting state in the body without requiring the patient to sharply cut back on food intake.

The researchers studied SGLT-2 inhibitors in a series of animal studies. First, they split the animals into two groups. One ate a normal diet and the other consumed a high fat diet. The high fat diet induced an insulin-resistant, diabetes-like state. They then split the animals into the three different cohorts. One group maintained their original diets. The second group maintained their original diets but also took SGLT-2 inhibitors. The third group matched the weight loss of group two through other methods, to confirm that any beneficial effects seen in group two were a result of SGLT-2 inhibitors and not weight loss in general. The researchers confirmed that the group given the medication saw a large boost to their metabolic processes due to the activation of pathways associated with fasting. "Lowering glucose by this mechanism shifts metabolism toward beneficial pathways that help to reduce fat accumulation in tissues. It causes the liver to think that it's in a fasting state and therefore a lot of pathways and genes are turned on that are similar to what you would see when someone is fasting."

These include pathways typically activated during situations that cause a lack of available nutrients in the body, such as exercise or calorie intake reduction. SGLT-2 inhibitors also blocked a pathway that can cause insulin resistance. The researchers also identified a new hormone mediator of SGLT-2 inhibitor treatment. Mice treated with SGLT-2 inhibitor medication had elevated levels of FGF-21, a hormone known to induce beneficial metabolic effects. Using mice lacking FGF-21, they found that FGF-21 was required for the weight loss and reduced body fat. FGF-21 did not play any role in the reduction of fat deposition in the liver. One mystery still remains, however: what are the specific mechanisms behind the reduction in cardiovascular disease risk observed in humans? This will be an important question for future studies.

SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms

SGLT2 inhibitors (SGLT2i) are unique antidiabetic drugs that promote urinary glucose loss and increase the urinary threshold for glucose reabsorption. As a result, plasma glucose levels are reduced and overall glycemic control is improved. Intriguingly, SGLT2i, including canagliflozin (CANA), have recently been shown to reduce cardiovascular and all-cause mortality in type 2 diabetes (T2D) and may improve hepatic steatosis and nonalcoholic fatty liver disease. The cellular actions of SGLT2i are distinct from those of other medications for T2D, such as insulin sensitizers and insulin secretagogues, which reduce blood glucose but increase glucose uptake and promote weight gain. By contrast, SGLT2i act in an insulin-independent manner to cause modest weight loss, promote fatty acid oxidation and ketogenesis, and increase hepatic glucose production, even after a single dose. The unique induction of fatty acid oxidation and ketogenesis by SGLT2i may contribute to not only beneficial outcomes, but also ketoacidosis reported with this medication class.

Here, we utilize an integrated transcriptomic-metabolomics approach to identify molecular mediators of CANA in nondiabetic mice with diet-induced obesity. We demonstrate that CANA modulates key nutrient-sensing pathways, with activation of 5′ AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR), without changing insulin or glucagon sensitivity or signaling. Moreover, CANA induces transcriptional reprogramming to activate catabolic pathways, increase fatty acid oxidation, reduce hepatic steatosis, and increase hepatic and plasma levels of the hepatokine FGF21. FGF21 is an important coordinator of fasting-induced metabolic responses and reduction in adiposity via increasing lipolysis, hepatic fatty acid oxidation, and ketogenesis. Given that these effects mirror many phenotypes induced by CANA, we hypothesized that FGF21 would be required for CANA action. Using FGF21-null mice, we demonstrate that FGF21 is not required for the metabolic switch toward a fasting-like catabolic state but is required to promote lipolysis and reduction in adiposity in response to SGLT2i.

Epigenetic clocks measure DNA methylation of sites on the genome that are patterned in much the same way in every individual of a given age. DNA methylation is an epigenetic marker that serves to regulate the production of protein from a specific gene. A range of different clocks have been constructed based on weighted assessments of methylation at various points on the genome, and the best of them can measure age quite accurately, to within a few years.

The clocks were built by working backwards from DNA methylation and age data, and it was discovered along the way that people with methylation patterns characteristic of an older age have a worse prognosis for age-related disease and mortality, or have a greater tendency to already exhibit age-related diseases. It is unclear, however, as to what exactly epigenetic clocks really are measuring. Which of the underlying forms of damage and consequent dysfunction, outlined in the SENS rejuvenation research proposals, lead to these DNA methylation changes? Some of them? All of them? No-one can presently say, and that is a challenge if the research community is to use epigenetic clocks to assess potential rejuvenation therapies.

The development of tools to diagnose and predict age-dependent risks has enormous significance in preventing age-related diseases and improving the health status of the elderly. The process of aging results in multiple changes at both the molecular and cellular level, including cellular senescence, telomere attrition, and epigenetic alterations. Among these hallmarks, telomere length, which experiences progressive shortening during replication of somatic cells, is a remarkable characteristic of aging and linked with age-related health status. However, recent evidence has revealed that the correlation between telomere length and age-related outcomes of individuals is low. Thus, investigators are still searching for other biomarkers that can be used in the prediction of age-related outcomes with higher accuracy.

Current studies have indicated that epigenetic changes comprise a significant component of the aging process. Epigenetics refer to the modulation of gene activity without any change in the genomic sequence. Well-studied epigenetic modifications include DNA methylation, histone modification, and non-coding RNA, with changes in dynamic DNA methylation found to be most associated with the aging process. In general, age-dependent changes in DNA methylation include global hypomethylation and region-specific hypermethylation.

Abundant studies have demonstrated a close relationship between DNA methylation and aging and longevity. These findings have impelled researchers to develop age predictors based on the correlation between methylation changes and chronological age. DNA methylation age, evaluated by these predictors, reflects the biological age of a person, which has a close association with individuals' health status and can be changed by multiple risk factors, such as smoking and obesity. Therefore, the difference between DNA methylation age and chronological age may be a promising tool in predicting disease risk and longevity potential in early life.

Link: https://doi.org/10.3389/fgene.2019.00107

The research materials here make a good companion piece to a recent study showing that exercise performance, physical fitness in other words, predicts mortality more accurately than age. In the study here, much the same analysis is carried in a different patient population, a sizable group with an average age of 75 at the study outset. Ten years after fitness testing was carried out, mortality data for the study population shows that those of greater fitness were significantly more likely to survive. We shouldn't need any more incentives than already exist to stay active and fit for as long as we can in live, but add this one to the mountain of evidence on the topic.

Doctors use cardiovascular risk factors to help guide decisions about preventive measures and medications. Previous studies have shown that quitting smoking and controlling blood pressure, cholesterol, and diabetes can reduce heart disease risk. However, most studies of cardiovascular risk factors have focused on middle-aged people, leaving a knowledge gap regarding the importance of these risk factors in older people.

The team analyzed medical records from more than 6,500 people aged 70 years and older who underwent an exercise stress test between 1991 and 2009. They assessed fitness based on patients' performance during the exercise stress test, which required patients to exercise on a treadmill as hard as they could. They divided patients into three groups reflecting their fitness based on the number of METs (metabolic equivalents, a measure of exercise workload) they achieved during the test: most fit (10 or more METs), moderately fit (six to 9.9 METs) and least fit (six or fewer METs). For this study, the researchers grouped patients with zero, one, two, or three or more cardiovascular risk factors.

On average, participants were 75 years old when they underwent the stress test. Researchers tracked the patients for an average of just under 10 years, during which time 39 percent of them died. Over this period, the researchers found higher fitness was associated with significantly increased rates of survival. The most fit individuals were more than twice as likely to be alive 10 years later compared with the least fit individuals. In contrast, a patient's total number of cardiovascular risk factors was not associated with their risk of death and patients with zero risk factors had essentially the same likelihood of dying as those with three or more risk factors. The study did not account for any changes in fitness level that the participants may have experienced over time. However, previous studies have suggested that improving fitness can help improve heart health, even late in life.

Link: https://www.eurekalert.org/pub_releases/2019-03/acoc-hfl030519.php

The accumulation of lingering senescence cells with age is apparently there to be discovered in every tissue in the body, and researchers are gathering a great deal of data now that it is generally accepted that these errant cells are one of the causes of aging. The overt signs of cellular senescence in a tissue are much the same throughout the body, even if there may well be significantly different classes of senescent cell still to be categorized. All senescent cells examined to date generate inflammatory, harmful secreted molecules that rouse the immune system, disrupt surrounding cell activities, destructively remodel the extracellular matrix, and more. All of this is a necessary part of regeneration when it takes place over the short term, but when the secretions of senescent cells continue without resolution, over years, the diseases, declines, and chronic inflammation of aging emerge.

In today's open access paper, researchers identify signs of cellular senescence in bone marrow cell populations as a contributing factor to the age-related decline of hematopoietic activity, the very necessary creation of immune and blood cells by hematopoietic stem cells. A reduced supply of new immune cells is one of the major contributing causes of age-related immunosenescence, the faltering of the immune system. The immune system is so fundamental to health that its fall into chronic inflammation and ineffectiveness may be a primary driver of human late-life mortality. Certainly, there is a wide range of evidence linking aspects of immune function with mortality in human cohorts.

What do we do about cellular senescence? We deploy senolytic therapies systemically throughout the body, targeting senescent cells for destruction by triggering apoptosis. The initial set of senolytic compounds used in research and early testing seem moderately effective in mice, clearing up to half of senescent cells from some tissues, and human data is starting to arrive this year. These compounds are cheap and easily obtained by those who don't wish to wait five to ten years for an expensive (and only maybe improved) version to emerge from the regulatory pathway of clinical trials. The research community will be kept quite busy in the years ahead by assessing cellular senescence, and then the removal of senescent cells, in the context of each and every decline of aging. But anyone willing to accept the risks of self-experimentation, after reading through the existing evidence and making an informed decision, can always choose to forge ahead today and try for themselves, to see what happens to their own age-related conditions.

An early-senescence state in aged mesenchymal stromal cells contributes to hematopoietic stem and progenitor cell clonogenic impairment through the activation of a pro-inflammatory program

Hematopoietic stem and progenitor cells (HSPC) can self-renew and differentiate into all blood components thus serving as a reservoir for mature blood cells throughout life. However, as we age, HSPC functionality is impaired with cells displaying a reduced capacity to maintain tissue homeostasis. Hematopoietic stem and progenitor cells reside in the bone marrow (BM) niche, and their function is supported by a variety of both hematopoietic and nonhematopoietic cell types, such as osteoblasts, adipocytes, endothelial, and mesenchymal stromal cells (MSC). Several studies highlighted the key role of MSC in regulating HSPC fate and promoting engraftment of the rare and more primitive hematopoietic stem cells (HSC). Indeed, changes in the cellular composition of the HSC niche during aging contribute to hematologic decline and involve decreased bone formation, enhanced adipogenesis, increased BM inflammation, and altered HSPC-MSC crosstalk.

Senescent cells accumulate during aging and contribute to tissue dysfunction and impaired tissue regeneration. Senescence is also characterized by increased SA-β-Gal activity, persistent DNA damage repair activation, and telomeric attrition. Moreover, senescent cells exhibit transcriptional activation of a senescent-associated secretory inflammatory phenotype collectively known as SASP. The robust secretion of SASP chemokines/cytokines triggers an inflammatory response that could reinforce senescence in a cell-autonomous fashion and be transferred to surrounding cells through paracrine mechanisms, to amplify the senescence response.

To date, the activation of a senescence program in human aged MSC and the interplay between aged MSC and HSPC remain to be elucidated. In this study, we successfully established human BM-derived MSC from young and elderly healthy donors. We investigated the effects of chronological age on MSC properties and found that MSC derived from aged healthy subjects show senescence-like features comprising an enlarged morphology, reduced proliferation capacity, delayed cell cycle progression, and increased levels of SA-β-Gal and lipofuscin. Importantly, we found that aged MSC activate a SASP-like program that contributes in a non cell autonomous manner to impair young HSPC clonogenicity by mediating an inflammatory state in HSPC.

Over the past decade, a growing body of evidence revealed that inflammatory stimuli alter HSPC fate and functionality by affecting HSPC proliferation/quiescence status, differentiation potential, or HSPC-niche interactions. In particular, it has been reported that chronic inflammation drives HSPC myeloid skewing and leads to HSPC exhaustion during aging. Our data indicate that the secretome of aged MSC may as well contribute to boost inflammation in HSPC in a paracrine fashion. However, further investigations are needed to dissect the role of individual SASP factors secreted by aged MSC on HSPC biology and to determine whether chronic exposure of young HSPC to MSC-derived inflammatory molecules may induce paracrine senescence in HSPC as previously described in other settings.

Forms of intermittent fasting and calorie restriction are quite effective at reducing inflammation, and the work done on fasting mimicking diets has gone a long way towards quantifying this effect. The goal was to find the 80/20 point on the line between mild calorie restriction and fasting, the most food one can eat and still obtain lasting benefits to metabolic health due to the usual reaction to an extended period of restricted calorie intake. (Which, per that research, is one day at 1000 kcal followed by four more days at 750 kcal per day, provided those calories are in the form of healthy food). Since lowered calorie intake has anti-inflammatory effects, it isn't surprising to see researchers investigating it in the context of inflammatory diseases. The work here is largely interesting for the continued focus on the degree to which the benefits of fasting emerge during the period of increased calorie intake afterwards, rather than during the fast.

A new study reports on the health benefits of periodic cycles of the diet for people with inflammation and indicated that the diet reversed inflammatory bowel disease (IBD) pathology in mice. Results showed that fasting-mimicking diet caused a reduction in intestinal inflammation and an increase in intestinal stem cells in part by promoting the expansion of beneficial gut microbiota. Study authors say the reversal of IBD pathology in mice, together with its anti-inflammatory effects demonstrated in a human clinical trial, indicate that the regimen has the potential to mitigate IBD.

For people with a poor diet, a "once in a while" fix is the periodic use of a low-calorie, plant-based diet that causes cells to act like the body is fasting. Earlier clinical trials allowed participants to consume between 750 and 1,100 calories per day over a five-day period and contained specific proportions of proteins, fats, and carbohydrates. Participants saw reduced risk factors for many life-threatening diseases. "We know that the fasting-mimicking diet is safer and easier than water-only fasting, but the big surprise from this study is that if you replace the fasting-mimicking diet, which includes pre-biotic ingredients, with water, we don't see the same benefits."

In the study, one group of mice adhered to a four-day fasting-mimicking diet by consuming approximately 50 percent of their normal caloric intake on the first day and 10 percent of their normal caloric intake from the second through fourth days. Another group fasted with a water-only diet for 48 hours. The study demonstrated that two cycles of a four-day fasting-mimicking diet followed by a normal diet appeared to be enough to mitigate some, and reverse other, IBD-associated pathologies or symptoms. In contrast, water-only fasting came up short, indicating that certain nutrients in the fasting-mimicking diet contribute to the microbial and anti-inflammatory changes necessary to maximize the effects of the fasting regimen.

The research team observed activation of stem cells and a regenerative effort in the colon and the small intestine, which increased significantly in length only in the presence of multiple cycles of the fasting-mimicking diet. They concluded that fasting primes the body for improvement, but it is the "re-feeding" that provides the opportunity to rebuild cells and tissues. "We've determined that the dietary components are contributing to the beneficial effects; it's not just about the cells of the human body but it's also about the microbes that are affected by both the fasting and the diet. The ingredients in the diet pushed the microbes to help the fasting maximize the benefits against IBD."

Link: https://news.usc.edu/154847/fasting-mimicking-diet-ibd-usc-stody/

Calorie restriction, reducing calorie intake by 40% or so while maintaining optimal micronutrient intake, is the most reliable way to upregulate all of the cellular maintenance processes that act to improve cell and tissue function. This response to famine evolved very early on in the history of life on our planet, and near all organisms assessed by the research community have a cellular metabolism that operates more efficiently when calories intake is restricted. While everyone should consider trying calorie restriction, given the health benefits it conveys, and given that it costs nothing, it isn't the path to a sizable extension of life span in our species. Efforts to recreate even thin slices of the metabolic response to calorie restriction have proven to be challenging, despite an investment of billions and decades, and even the best present development programs achieve little in the grand scheme of what might be possible given better approaches to the problem of aging. They will only modestly slow aging, not radically change the length of human life.

The number of calories a person eats directly influences the performance of different cells. One experiment on mice shows how a low calorie diet can protect the brain from neuronal cell death associated with diseases such as Alzheimer's, Parkinson's, epilepsy, and cerebral vascular accident (CVA). The mice were divided into two groups. The researchers calculated the average number of calories the group with no caloric restrictions would eat and then fed the other group 40% fewer calories. After 14 weeks, mice belonging to the two groups were given an injection containing a substance known to cause seizures, damage, and neuronal cell death.

While the animals in the group that had no dietary restrictions had seizures, the animals whose calories had been restricted did not. The researchers then studied what occurred in vitro. To do that, they isolated the organelles called mitochondria of the brain cells of the mice, which were also divided into two groups: those that had unrestricted diets and those that had restricted diets. When calcium was introduced to the medium, they noted that uptake was greater in the mitochondria belonging to the group that had ingested fewer calories. Mitochondria are the organelles responsible for energy generation in cells. In the case of the mice subjected to a calorie restricted diet, mitochondria increased the calcium uptake capacity in situations where the level of that mineral was pathologically high.

In the pancreas, caloric restriction has shown to be capable of improving cell response to increased levels of blood glucose. The researchers reached this conclusion after conducting experiments using beta cells that remain in the pancreatic islets and are responsible for producing insulin. Blood serum from mice subjected to a variety of diets, similar to the study on the effects of caloric restriction on neurons, was used to nourish the cells cultivated in vitro. In the cells treated with the serum of animals that ate fewer calories, insulin secretion through the beta cells occurred normally: low when glucose was low and high when glucose was elevated. This did not occur in the animals that ate more calories (and became obese). The experiment showed that there may be a circulating blood factor that acutely modifies beta cell function.

Researchers have again raised the hypothesis of whether the phenomenon is related to the mitochondria, since insulin secretion depends on the availability of ATP (adenosine triphosphate, the molecule that stores energy) in the cell. When they measured oxygen consumption by the two groups of cells, they observed that it was higher in cells that received serum from animals subjected to caloric restriction. Since respiration is responsible for the release of insulin during peak glucose, it was a sign that the cells generated more ATP under that condition. Other experiments have also shown that the mitochondria of cells treated with serum from animals subjected to caloric restriction exchanged more material with each other, which made them more efficient.

Link: http://fapesp.br/week2019/london/news/diets-consisting-of-fewer-calories-improve-cell-performance