Fight Aging! Newsletter, November 12th 2018

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • European Longevity Conferences in November
  • Notes on the 2018 Longevity Forum in London
  • SREBP-1c Mediated Alterations in Fat Metabolism are Essential to Life Extension Achieved via Calorie Restriction
  • A Distinct Population of Smooth Muscle Cells is Associated with Vascular Disease
  • A Mechanism by Which Hypertension Accelerates Atherosclerosis
  • Greater Cancer Risk for Taller People is Near Entirely Due to Having More Cells
  • The Number of Neurons in the Cortex is Strongly Associated with Species Longevity
  • Another Recent Study Assesses the Financial Burden of Excess Fat Tissue
  • Asking Rationalists to be Rational About Treating Aging as a Medical Condition
  • Hunter-Gatherer Populations Highlight the Self-Sabotage of Health in Wealthier Societies
  • The State of Animal Models for the Hallmarks of Aging
  • The First Longevity Leaders Conference will be Held in London in 2019
  • Higher Protein Intake Associated with Slower Onset of Disability in Old People
  • Calorie Restriction Slows Loss of Gut Integrity with Age
  • Fibroblasts in Old Skin Lose their Functional Identity

European Longevity Conferences in November

By stretching the definition of European to include the United Kingdom, a topic about which everyone involved seems ambivalent, we can say that November opens with a set of three European longevity conferences, all within a few days of one another. The first is in London, running today, the second in Valencia, the third in Brussels. Conferences and concrete are metrics by which one can judge the health of a field: the more events, the more interest, and the more buildings under construction at various institutions, the more advanced the state of funding. First the conferences, and then the concrete, years later, if the field continues to grow and become successful.

It is still the case that most people remain to be informed that treating aging as a medical condition is a very real possibility for the near future. Most people remain to be persuaded that preventing death and disability by aging is of great importance, indeed the most important project that our species might undertake. Yet those very same people will be among the majority that will suffer and die from aging. Aging is by far the greatest cause of harm, loss, and cost in the world, its consequences many times larger than the next most severe affliction affecting humanity. We stand on the verge of doing something about this, but the silent majority doesn't know and doesn't care. The world still needs to be awoken.

Thus conferences, networking, advocacy, and spreading the word. This is an important juncture in the growth of the rejuvenation research community, as investment in the clinical development of senolytics, the first of the new classes of rejuvenation therapies outlined in the SENS vision for the treatment of aging, is pulling new groups into this sphere at an increasing pace. Rejuvenation through periodic repair of the molecular damage that causes aging will be the basis for a vast industry of medicine, larger than anything that has come before. Everyone adult is a customer at some price point. The first successful companies to deploy working rejuvenation therapies will become behemoths capable of funding the basic science to finalize all of the SENS rejuvenation biotechnologies. If the world can be awoken, if the resources for growth obtained, then the next few decades in the medical life sciences will prove to be a wild ride indeed.

The Longevity Forum, November 5th 2018

Our inaugural forum, which takes place on 5 November 2018 in London, is a true public and private partnership which will address a host of issues pertaining to the full human life cycle - both from a scientific and a social science perspective. It will bring together key opinion leaders from the worlds of government, business, science and education, to identify immediate and long-term priorities for The Longevity Forum.

Longevity World Forum, November 7th-8th, 2018

Life expectancy for humankind has increased considerably in the last 100 years. In fact, now we wonder about the limit of human longevity. Living better and longer is one of the main concerns of our society as well as one of the main objectives of contemporary medicine. Thus, the scientific community is working really hard to bring advances in this sense and to broaden knowledge about the genetic basis of human longevity and the biological mechanisms related to aging. Scientists want to find therapeutic strategies to prolong life and assure a quality standard. All in all, Longevity World Forum is conceived as a new space for experts to collaborate and develop knowledge about this field.

Fourth Eurosymposium on Healthy Ageing, November 8th-10th 2018

The defeat of aging lies within our collective grasp. It's time to seize this remarkable opportunity. The Eurosymposium on Healthy Ageing proclaims the possibility and the imperative of a moonshot project to overcome all age-related diseases within 25 years by tackling aging as their root cause. The result will be a world where healthcare is far less expensive; where human well-being can be radically extended; where people place greater value on the environment and on peace, in view of their expectation of much longer lives; where the right to life is more precious than ever, because life is longer.

Key steps in this initiative will include a paradigm shift stressing the need for research on aging itself, rather than only on individual diseases of old age; the removal of regulatory and other barriers which prevent or disincentivize companies from developing treatments for aging itself; an accelerated program to test anti-aging interventions on a much larger scale than anything that exists at the moment, leading to multiple human clinical trials of genuine rejuvenation biotechnologies by 2021. These programs will require a coordinated effort at national and international level, integrating diverse existing and novel research approaches. They need to be financed by both public and private organizations, and create inclusive, affordable solutions available on equal terms to everybody.

Notes on the 2018 Longevity Forum in London

The Longevity Forum, hosted by investor Jim Mellon and company yesterday in London, was a reminder that we still have a way to go when it comes to guiding the conversation on longevity and rejuvenation in a useful direction. On the one hand, most people give medicine and aging little serious thought until it is too late, and if we want large-scale funding for the goal of human rejuvenation through realization of the SENS research agenda, then the public at large really has to be on board in the same way that they are reflexively in favor of doing something about cancer and Alzheimer's disease. On the other hand, the first reaction of many people when presented with the concept of enhanced human longevity is to fixate on line items that really do not matter in the grand scheme of things: whether retirement will still exist; will life insurance companies have to change their ways; will some particular demographic gain slightly more or slightly less than another as a result of progress in medicine. None of these points matter anywhere near as much as does the act of building the therapies that will save lives and improve lives.

I should probably disclose that I am a technological determinist, in the sense that it is technology that determines society. People will adapt to new capabilities quite rapidly, as illustrated by any number of world-changing advances in communications, transport, and medicine introduced and enthusiastically embraced over the past few centuries. The shape of society will shift in response to those new capabilities. Building the technology is the first, foremost, and only goal: let the rejuvenation therapies be built and distributed, and let the world adapt to the wonders of a longer, healthier life. Insofar as we have to talk about it ahead of time, that talking should focus on whatever is needed in order to direct resources to the appropriate tasks of research and development.

But clearly others feel differently, in that broader discussions should take place, or that there is a process of awareness and coming to terms that must be undertaken. Expectations must be managed, and perhaps that is really all this comes down to at the end of the day. People don't want to be surprised, whether they are managing billions in life insurance liabilities, or managing their own career and little else. If the status quo today was that we all knew that rejuvenation was arriving soon, then that would be the status quo and everyone would be fine with it. Our job as advocates is, in some sense, to make this the status quo.

The Longevity Forum brought together scientists, insurance and medical industry functionaries, biotechnology investors, former politicians, people with interests in philosophy and self-empowerment, and a variety of less easily described types. There was a row of journalists in the back of the auditorium, heads down and taking notes. The scientific content was kept deliberately lightweight, and the focus was more on what this business of longer healthy lives means for people who live in the mundane world of pensions, life insurance, planning for retirement, and coping with the ugly realities of late life disability. I will say that these are all earnest folk in their own ways and their own bailiwicks, but their day to day concerns are about to be upended in the deluge. The technology has arrived, senolytic therapies to clear senescent cells exist, now, today, and there is no time to be concerned with what will be. By the time any bureaucracy has fully engaged with the question, we will be looking at the dawn of the age of rejuvenation in the rear view mirror.

Large financial institutions are not well positioned for any sort of upward leap in life expectancy in old age, of the sort that will take place the moment that widespread use of senolytic drugs occurs. They can cope with a slightly more aggressive upward trend, and indeed have been gearing up for that for quite some time. But a sudden leap? The result will make the bailouts of other industries in the past few decades look anemic. That is of course no reason to stop. Life for everyone is more important than the financial health of any given group of businesses earnestly engaged in making a severe strategic error. Those that serve poorly should become bankrupt and go under, though sadly the costs are all too often socialized these days. Nothing that was said by the representatives of these industries at the Longevity Forum gives me any hope that it will happen differently; those present either understood but were in no position to make changes, or did not give much weight to the possibility of large upward leaps in life expectancy.

I think one of the reasons that this decimation of the pensions and life insurance industries will happen is because many of the figureheads of the research community are very conservative in their view of timelines and potential. Eric Verdin is an interesting case in point; he was presenting at the Longevity Forum to give an overview of work at the Buck Institute. Verdin makes the case that we are not all that far in to the standard 50 year cycle for longevity-related technologies, and it takes at least 20 years to get anything moving in earnest, pointing to stem cell therapies as an example. On that basis he, like a number of others, sees only incremental advances ahead in human longevity. At the very same time, however, he is quite aware of senolytics, given that it arose in part at the Buck Institute, and touts that work as important. But I have to think that he doesn't see it as any being different than, say, calorie restriction mimetics, in terms of how one can talk about the prospects for human health and longevity. This seems like a deep and important error to me. These two classes of therapy are a world apart. One repairs a form of damage that causes aging, the other adjusts metabolism to slightly slow the onset of further damage. The size of effect and reliability of results are night and day.

In any case, to return to the original point, if one wants to swing society into line with the goal of building an industry whose products will enable people to live much longer in good health, then the established way of going about doing so involves efforts that look a lot like the Longevity Forum. Thus I expect to see more of this sort of thing in the years ahead, and not just in London. The goal of building an industry is far greater than just succeeding with a couple of startup biotechnology companies, and will, even initially, require billions in investment in new medical and research infrastructure. While the core technology demonstrations of the SENS rejuvenation research programs, to produce an old mouse that exhibits comprehensive rejuvenation and a doubling of remaining life span, could be achieved now for something less than a billion spent over a decade, it is vastly more expensive to translate that work into human medicine and then provide it to the world. That requires very large, very conservative organizations to play their part, and they tend to follow public opinion, not lead it.

At one point near the end of the event I found myself advocating senolytics to one of the non-scientists present, a noted figure who runs a charity to help old people with their physical limitations - and is thus in a position to do a great deal of good as rejuvenation therapies emerge. I was forcefully reminded by the resulting polite rejection that people outside our community really cannot tell the difference between snake oil and real rejuvenation therapies. To them a suggestion to look into senolytics, because amazing things are happening in the laboratory and among self-experimenters, sounds no different from a pitch for supplements made by any random fraud in the anti-aging marketplace. Those on the outside are wary, or disinterested, and will be slow to come around. The need for patient advocacy doesn't end just because a treatment exists, and that includes the persuasion of existing patient advocates who work with old people. It seems a terrible thing to me that so many millions are suffering right now, and could make an educated choice on the risks and the rewards to seek benefit from any of the easily available senolytics, if they only knew what we know.

The Longevity Forum is a charitable concern, and part of its remit is not just to bring together the insiders and the outsiders in the matter of longevity science, but also to bring together public, private, and charitable concerns in order to advance their agendas. Charities for scleroderma and premature ovarian insufficiency presented at the event. Both conditions are more subtly age-related than the most common age-related conditions that we are all more familiar with. The latter of the two looks a lot like a very selective progeria in many ways, both superficially and in its biochemistry. There was some discussion of ways in which those present might help. Among those who could offer assistance on the technical front was Alex Zhavoronkov of In Silico Medicine. He presented on some of the capabilities of his company, using deep learning techniques with genetic and epigenetic data sets to find small molecule drug candidates and biomarkers that might accelerate research and development. This is particularly applicable to medical conditions wherein the research community has struggled to gain a good understanding of the underlying mechanisms and causes. It is true, however, that pharmaceutical development in general is one of the least efficient processes in medicine, regardless of the target condition. It is an area ripe for disruption, even if that disruption is limited to creating a very cheap, efficient source of candidate compounds for arbitrary medical conditions.

The formal event ended with a panel discussion on "life well lived." Do people really need to be told how to live? Will the applicability of the wisdom of the ancients really change in the slightest given another few decades of life? One day in the next few years doctors will start prescribing senolytics. Life spans will increase. A lot of ink will be spilled on viewpoints that are ultimately pointless and that will vanish from memory near immediately. Society will continue. But we still, it seems, need to be in the business of managing expectations as well as building new biotechnology.

SREBP-1c Mediated Alterations in Fat Metabolism are Essential to Life Extension Achieved via Calorie Restriction

One of the approaches taken in efforts to understand a complex system such as metabolism is to break specific components, one by one, and observe the results: disable a gene, block the interactions of a protein, and so forth. This technique is widely used in investigations of calorie restriction, particularly regarding the way in which calorie restriction extends life span in short-lived species such as mice. It allows researchers to narrow the list of mechanisms and regulators that are most important in the way in which metabolism determines variations in the pace of aging. Calorie restriction is challenging as a topic for research, as near every aspect of cellular metabolism is changed by the adoption of a low calorie diet. While most of the important processes are known at a high level, decades of research have yet to result in a comprehensive understanding of the detailed interaction between metabolism and aging.

Today's open access paper reviews one of the mechanisms known to be vital to the operation of calorie restriction. If it is disabled, then calorie restriction no longer functions to extend life in mice. The mechanism involves alterations in the metabolism of white fat tissue via a master regulator that influences lipid storage and mitochondrial function in that tissue. Fat is metabolically active and via signals can influence the rest of the body in a variety of ways. It is evidently the case that eating fewer calories has a sizable impact on fat tissue, but it is interesting to see just how far researchers have progressed into understanding what that means at the detail level. The other vital mechanisms of calorie restriction are related to autophagy, the cellular processes of maintenance that recycle damaged proteins and cellular structures. Like many of the other ways to modestly slow aging in short-lived species, calorie restriction upregulates autophagy, and indeed requires the correct function of autophagy in order to extend life. When autophagy is disabled, calorie restriction fails to extend life.

SREBP-1c-Dependent Metabolic Remodeling of White Adipose Tissue by Caloric Restriction

Caloric restriction (CR), also known as dietary restriction, is a simple and reproducible manipulation that delays the onset of many age-related pathophysiological changes and extends both median and maximum lifespan. The life-extending effect of CR is observed in several species, including yeast, worms and mammals; hence, CR has been widely investigated in aging research. In general, CR animals exhibit low body temperature and plasma insulin, and high plasma dehydroepiandrosterone sulfate (DHEAS). Interestingly, it has been reported that humans with this phenotype live longer than their counterparts. Furthermore, a recent report has revealed the effectiveness of CR in non-human primates, implying that CR can be also beneficial for humans.

Previous studies have suggested that the beneficial effects of CR may involve various mechanisms; for example, the suppression of growth hormone/insulin-like growth factor (GH/IGF-1) signaling, reduction of mechanistic target of rapamycin complex 1 activity, activation of sirtuin, enhancement of mitochondrial biogenesis, attenuation of oxidative and other types of stress, suppression of inflammation, and alteration of the gut microbiome. Thus, the mechanisms underpinning the effects of CR are complex and diverse, and further research is required for them to be fully elucidated.

White adipose tissue (WAT) is a major site of energy storage in the form of triglyceride (TG), but WAT has also become established as an endocrine tissue that secretes adipokines. It is accepted that the characteristics of adipocytes and their secretory profile differ according to their size. Large adipocytes storing a large amount of TG. In contrast, small adipocytes secrete more adiponectin. Moreover, small adipocytes are more sensitive to insulin and play a buffering role for whole-body lipids by absorbing them after a meal and releasing them in the fasting state. Thus, differences in the characteristics of WAT can influence whole-body metabolism.

Recent studies have demonstrated that several models of genetic modification in WAT are associated with differences in lifespan. For example, fat-specific insulin receptor knockout (FIRKO) mice display lower adiposity, enhanced mitochondrial biogenesis, and extended lifespan, compared with a control group. In addition, genetic manipulation of master regulators of adipocyte differentiation in mice is known to alter lifespan. It has also been reported that differences in adipokine secretion profiles affect lifespan. For instance, liver-specific adiponectin transgenic mice are resistant to high-calorie diet-induced obesity and demonstrate an extended lifespan.

CR prevents age-induced adiposity by lowering plasma insulin and leptin concentration and raising adiponectin concentration, while also reducing the size of adipocytes in WAT. Therefore, we hypothesized that the beneficial effects of CR may be partially mediated by functional alterations in WAT. In the process of testing this hypothesis, we identified the sterol regulatory element-binding protein 1c (SREBP-1c), a master transcriptional regulator of lipogenic gene expression, as a mediator of CR. These findings were validated by showing that CR failed to upregulate factors involved in fatty acid biosynthesis and to extend longevity in SREBP-1c knockout mice. Furthermore, we revealed that SREBP-1c is implicated in CR-associated mitochondrial activation through the upregulation of PGC-1α, a master regulator of mitochondrial biogenesis. Notably, these CR-associated phenotypes were observed only in WAT.

A Distinct Population of Smooth Muscle Cells is Associated with Vascular Disease

Researchers have identified a marker for a small population of smooth muscle cells in blood vessel walls that show up in larger numbers in cases of vascular disease, such as atherosclerosis. These cells may be dysfunctional in the sense that they (a) appear to be involved in inflammatory signaling and (b) lose the normal behavior of smooth muscle tissue. My first thought on reading the abstract of the paper was that this may be a senescent population, as inflammation and disruption of tissue function are quite characteristic of the bad behavior of senescent cells. On closer reading that sounds less likely, however. These may well be cells that are engaged in repair and regrowth activities, which also tend to involve at least short term inflammation alongside significant changes in cell activities.

Are these cells harmful, or are they responding in a beneficial way? That may depend on context; it might be the case that they are initially beneficial, but in the later stages of disease progression they become a problem, and contribute to the disease state. The discovery of a marker allows technologies such as the Oisin Biotechnologies suicide gene therapy platform to target these cells for destruction. Evaluating the outcome in mice is the fastest way to determine whether or not the cells are harmful, and whether or not this varies with disease progression. This is the case for the removal of a broad range of other potentially harmful cell populations found in older individuals. Most of these projects are easy to describe, and all of the necessary preliminary work of identifying the cells has been accomplished, but still no-one is even thinking about undertaking the work. The challenge here is that there is too little philanthropy, too few entrepreneurs, and too little venture funding to carry out anywhere as much as many projects as should be underway right now.

Observation of blood vessel cells changing function could lead to early detection of blocked arteries

The muscle cells that line the blood vessels have long been known to multi-task. While their main function is pumping blood through the body, they are also involved in patching up injuries in the blood vessels. Overzealous switching of these cells from the pumping to the repair mode can lead to atherosclerosis, resulting in the formation of plaques in the blood vessels that block the blood flow. Using state-of-the art genomics technologies, an interdisciplinary team of researchers has caught a tiny number of vascular muscle cells in mouse blood vessels in the act of switching and described their molecular properties. The researchers used an innovative methodology known as single-cell RNA-sequencing, which allows them to track the activity of most genes in the genome in hundreds of individual vascular muscle cells.

"We knew that although these cells in healthy tissues look similar to each other, they are actually quite a mixed bag at the molecular level. However, when we got the results, a very small number of cells in the vessel really stood out. These cells lost the activity of typical muscle cell genes to various degrees, and instead expressed a gene called that is best known to mark stem cells, the body's master cells." Knowing the molecular profile of these unusual cells has made it possible to study their behaviour in disease. Researchers have confirmed that these cells become much more numerous in damaged blood vessels and in atherosclerotic plaques, as would be expected from switching cells. "Theoretically, seeing an increase in the numbers of switching cells in otherwise healthy vessels should raise an alarm. Likewise, knowing the molecular features of these cells may help selectively target them with specific drugs."

Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels

Vascular smooth muscle cells (VSMCs) show pronounced heterogeneity across and within vascular beds, with direct implications for their function in injury response and atherosclerosis. Here we combine single-cell transcriptomics with lineage tracing to examine VSMC heterogeneity in healthy mouse vessels. The transcriptional profiles of single VSMCs consistently reflect their region-specific developmental history and show heterogeneous expression of vascular disease-associated genes involved in inflammation, adhesion, and migration.

We detect a rare population of VSMC-lineage cells that express the multipotent progenitor marker Sca1, progressively downregulate contractile VSMC genes and upregulate genes associated with VSMC response to inflammation and growth factors. We find that Sca1 upregulation is a hallmark of VSMCs undergoing phenotypic switching in vitro and in vivo, and reveal an equivalent population of Sca1-positive VSMC-lineage cells in atherosclerotic plaques. Together, our analyses identify disease-relevant transcriptional signatures in VSMC-lineage cells in healthy blood vessels, with implications for disease susceptibility, diagnosis, and prevention.

A Mechanism by Which Hypertension Accelerates Atherosclerosis

The raised blood pressure of old age is known as hypertension, and it is predominantly caused by dysfunction in blood vessel walls: cross-links, calcification, and loss of elastin cause reduced elasticity, while smooth muscle cells lose their capacity to act for a variety of other reasons. When blood vessels can no longer correctly react to circumstances by contracting and dilating to an appropriate degree, then the whole system of pressure control is thrown off, and higher blood pressure is the result.

Atherosclerosis, on the other hand, is the progressive formation of fatty plaques in blood vessel walls. This narrows and weakens blood vessels. Atherosclerosis interacts with hypertension in the obvious way: weakened blood vessels and fragile plaques are more likely to suffer catastrophic structural failure in a high pressure environment, leading to a fatal stroke or heart attack. Just considering this interaction, it is clear that hypertension raises the risk of death and shortens life expectancy. This isn't the only interaction, however, just the most direct one. In addition, hypertension accelerates the growth of atherosclerotic plaques, and the reasons for this are not fully understood.

In the research materials noted here, the authors report on an association between a particular subset of cases of hypertension and the pace at which immune cells known as monocytes arrive at atherosclerotic plaques in order to try to clean them up. Once embedded into the blood vessel wall, monocytes transform into macrophages. Plaques grow because these macrophages become overwhelmed by oxidized lipids, fail in their task of rescue, and die. Worse, many become inflammatory, senescent foam cells that linger to secrete signals that call in more of their peers. The bulk of a plaque is cell debris, and atherosclerosis is really a form of runaway garbage catastrophe. Once things get to the tipping point, the end is inevitable. In some cases, hypertension moves that tipping point in an undesirable direction by causing the production of more monocytes.

Neural driven blood pressure accelerates atherosclerotic cardiovascular disease through over production of monocytes

Atherosclerotic cardiovascular disease is a build-up of cholesterol plaque in the walls of arteries, causing obstruction of blood flow. Scientists have found that high blood pressure caused by specific signalling from the brain promotes heart disease by altering stem cells within the bone marrow. The results demonstrate how an overactive sympathetic nervous system that causes elevated blood pressure can instruct bone marrow stem cells to produce more white blood cells that clog up blood vessels.

"We now know that changes in the immune system contribute significantly to heart disease. We aimed to determine how the sympathetic nervous system through the brain directly promotes atherosclerosis in the setting of hypertension. We have discovered that this form of high blood pressure, often associated with stress, causes changes within the bone marrow leading to increased white blood cells circulating though our vessels. This is significant as the general view of hypertension is that it is mainly a disease of the blood vessels, which means other heart damaging events are missed." The team is now exploring the specific molecules involved, which may shed light as to why some current therapies are ineffective.

Chronic sympathetic driven hypertension promotes atherosclerosis by enhancing hematopoiesis

Hypertension is a major, independent risk factor for atherosclerotic cardiovascular disease. However, this pathology can arise through multiple pathways, which could influence vascular disease through distinct mechanisms. An overactive sympathetic nervous system is a dominant pathway that can precipitate in elevated blood pressure. We aimed to determine how the sympathetic nervous system directly promotes atherosclerosis in the setting of hypertension. We used a mouse model of sympathetic nervous system-driven hypertension on the atherosclerotic-prone apolipoprotein E deficient background. When mice were placed on a western type diet for 16 weeks we showed the evolution of unstable atherosclerotic lesions. Fortuitously, the changes in lesion composition were independent of endothelial dysfunction, allowing for the discovery of alternative mechanisms.

With the use of flow cytometry and bone marrow imaging, we found that sympathetic activation caused deterioration of the hematopoietic stem and progenitor cell niche in the bone marrow, promoting the liberation of these cells into the circulation and extramedullary hematopoiesis in the spleen. Specifically, sympathetic activation reduced the abundance of key hematopoietic stem and progenitor cell niche cells, sinusoidal endothelial cells, and osteoblasts. Additionally, sympathetic bone marrow activity prompted neutrophils to secrete proteases to cleave the hematopoietic stem and progenitor cell surface receptor CXCR4. All these effects could be reversed using the β-blocker propranolol during the feeding period. These findings suggest that elevated blood pressure driven by the sympathetic nervous system can influence mechanisms that modulate the hematopoietic system to promote atherosclerosis and contribute to cardiovascular events.

Greater Cancer Risk for Taller People is Near Entirely Due to Having More Cells

There has been some debate in the research community as to whether the observed relationship between cancer risk and height in our species is due to (a) taller people having more cells, and thus more chances to suffer a cancerous mutation, or (b) some more indirect factor, such as, for example, the role of growth hormone in cellular metabolism. The author of this study marshals data to argue convincingly for the former hypothesis, for most forms of cancer.

The multistage model of carcinogenesis predicts cancer risk will increase with tissue size, since more cells provide more targets for oncogenic somatic mutation. However, this increase is not seen among mammal species of different sizes (Peto's paradox), a paradox argued to be due to larger species evolving added cancer suppression. If this explanation is correct, the cell number effect is still expected within species.

Consistent with this, the hazard ratio for overall cancer risk per 10cm increase in human height (HR10) is about 1.1, indicating a 10% increase in cancer risk per 10cm; however, an alternative explanation invokes an indirect effect of height, with factors that increase cancer risk independently increasing adult height.

The data from four large-scale surveillance projects on 23 cancer categories were tested against quantitative predictions of the cell-number hypothesis, predictions that were accurately supported. For overall cancer risk the HR10 predicted versus observed was 1.13 versus 1.12 for women and 1.11 versus 1.09 for men, suggesting that cell number variation provides a null hypothesis for assessing height effects.

Melanoma showed an unexpectedly strong relationship to height, indicating an additional effect, perhaps due to an increasing cell division rate mediated through increasing IGF-I with height. Similarly, only about one-third of the higher incidence of non-reproductive cancers in men versus women can be explained by cell number. The cancer risks of obesity are not correlated with effects of height, consistent with different primary causation.

The Number of Neurons in the Cortex is Strongly Associated with Species Longevity

Researchers recently reported a most interesting finding: there is a good correlation between the number of neurons in the cortex and life span when comparing species. This holds up between classes of species, as well for a number of well known exceptions to other associations between physical characteristics and life span. For example, you might compare these results with the relationship between metabolic rate, mitochondrial composition, and life span that largely holds in mammals, save for bats, which are distinguished by their ability to fly. Flight imposes enormous demands on metabolism, and flying species are as a result biochemically quite different from even near cousin flightless species. Further afield in the taxonomic tree of life, birds tend to have far greater life spans than similarly sized mammals, and once again this is probably because of the demands of flight. Nonetheless, this association with cortical neuron count holds up well for birds and mammals alike. Why does this relationship exist? At this point researchers have nothing but educated guesses. I would imagine that we will hear more on this topic in the years ahead, however.

Whether you're looking at birds or primates or humans, the number of neurons that you find in the cortex of a species predicts around 75 percent of all of the variation in longevity across species. Body size and metabolism, in comparison, to usual standards for comparing animals, only predicted between 20-30 percent of longevity depending on species, and left many inconsistencies, like birds that live ten times longer than mammals of same size. Most importantly, humans were considered to be a "special" evolutionary oddity, with long childhood and postmenopausal periods. But this research finds that is not accurate. Humans take just as long to mature as expected of their number of cortical neurons - and live just as long as expected thereafter.

Researchers examined more than 700 warm-blooded animal species from the AnAge database which collects comprehensive longevity records. They then compared these records with data on the number of neurons in the brains of different species of animals. The researchers found that parrots and songbirds, including corvids, live systematically longer than primates of similar body mass, which in turn live longer than non-primate mammals of similar body mass. Previous studies determining what brains are made of showed that parrots and songbirds have more cortical neurons than similar-sized primates, which have more cortical neurons than any other mammal of comparable body size.

"The more cortical neurons a species has, the longer it lives - doesn't matter if it is a bird, a primate, or some other mammal, how large it is, and how fast it burns energy. It makes sense that the more neurons you have in the cortex, the longer it should take a species to reach that point where it's not only physiologically mature, but also mentally capable of being independent. The delay also gives those species with more cortical neurons more time to learn from experience, as they interact with the environment." What is the link between having more neurons in the cortex and living longer lives? That's the new big question researchers need to tackle.

Another Recent Study Assesses the Financial Burden of Excess Fat Tissue

The personal cost of being overweight or obese is sizable, even when considering only financial matters, the greater expenditure on medical needs and the opportunity costs that accompany sickness and loss of capacity. Additional weight in the form of visceral fat tissue both shortens life expectancy and increases lifetime medical expense, this much is well established in the scientific literature. Summing those costs over the entire population produces some staggeringly large numbers. Those numbers can vary widely depending on the assumptions and what is included; those here are on the high end. Yet the cost of excess weight is just a tiny fraction of the cost of degenerative aging as a whole, and it largely arises because being overweight makes the process of aging incrementally worse and incrementally faster.

The impact of obesity and overweight on the U.S. economy has eclipsed 1.7 trillion, an amount equivalent to 9.3 percent of the nation's gross domestic product, according to a new report on the role excess weight plays in the prevalence and cost of chronic diseases. The estimate includes 480.7 billion in direct health-care costs and 1.24 trillion in lost productivity, as documented in America's Obesity Crisis: The Health and Economic Impact of Excess Weight. The study draws on research that shows how overweight and obesity elevate the risk of diseases such as breast cancer, heart disease, and osteoarthritis, and estimates the cost of medical treatment and lost productivity for each disease.

For example, the treatment cost for all type 2 diabetes cases - one of the most prevalent chronic diseases connected to excess weight - was 121 billion and indirect costs were 215 billion. On an individual basis, that comes to 7,109 in treatment costs per patient and 12,633 in productivity costs. America's Obesity Crisis assesses the role excess weight plays in the prevalence of 23 chronic diseases and the economic consequences that result. To mention a few, obesity and overweight are linked to 75 percent of osteoarthritis cases, 64 percent of type 2 diabetes cases, and 73 percent of kidney disease cases. "Despite the billions spent each year on public health programs and consumer weight-loss products, the situation isn't improving. A new approach is needed."

Asking Rationalists to be Rational About Treating Aging as a Medical Condition

The rationalist and effective altruism communities overlap to a considerable degree, and do engage with the goal of radical life extension through the development of rejuvenation therapies, but not to the degree that I think would be rational. The only rational use for excess capital in this day and age is purchasing an acceleration in the development of rejuvenation biotechnology, on the grounds being alive and healthy enables all other options. That acceleration can be achieved through philanthropy, via support of the SENS Research Foundation, Methuselah Foundation, and similar organizations, or via investment in startups focused on the development rejuvenation therapies. But it can be achieved, and that is perhaps the point that hasn't yet sunk in in a large enough fraction of people.

As our ability to affect the aging processes has been dramatically improved within the past decade, now is an excellent time for rationalists to consider new evidence regarding the necessity and feasibility of rejuvenation biotechnology. The amount of harm caused by aging is immense from a human standpoint. It is, by far, the greatest threat to living people today, even in the most violent of countries. (It has long since dethroned the previous all-time killer, infectious disease, which we did something about.) In a world with untreated aging, everyone who does not die of something else will suffer from decades of declining health. Death is the inevitable result.

Aging is a global tragedy from an economic standpoint as well. Aging is the largest driver of healthcare costs in the United States. As birthrates remain low and unhealthy lifespans remain relatively long, the proportion of the economy devoted to taking care of older people can only increase. This economic burden represents an enormous expenditure of human labor, as large amounts of money and time are spent on keeping people alive as their bodies slowly fail them.

Fifteen years ago, the idea of intervening against aging through rejuvenation biotechnology was widely considered unfeasible or outside of human ability; today, it is mainstream science. The Hallmarks of Aging is one of the most frequently cited papers in biology. A wide variety of researchers at prestigious universities are actively involved in pursuing rejuvenation biotechnology therapies. Multiple biotechnology companies are developing interventions against the Hallmarks of Aging, each one of which has at least one partial intervention currently in development. For any given person, it is possible that partial interventions may delay enough of the aging processes long enough for further interventions to allow for more healthy years of life, until, ultimately, a comprehensive suite of therapies is developed to control all of the aging processes. This concept is called longevity escape velocity.

Unfortunately, aging is an enormous problem, not just in terms of the harms it does but in the number of specific therapies that will need to be successfully developed in order to completely control it. The current amount of effort is significant but not enough to bring about the medical control of aging as soon as would otherwise be possible. As a rationalist, you know better than to suffer from the bystander effect, waiting for someone else to do what needs doing. If you have the aptitude and are entering college, consider becoming a researcher yourself. Alternatively, you can aid advocacy efforts, fund research efforts, or, if you are an investor, finance the development of rejuvenation biotechnology companies.

Hunter-Gatherer Populations Highlight the Self-Sabotage of Health in Wealthier Societies

Modern hunter-gatherer societies are located in the poorer parts of the world, and thus still face challenges in the control of infectious disease. When it comes to age-related disease they can be notably better off than those of us in the typist-shopper societies of wealthier regions, however. This, I would say, has less to do with the components of diet and more to do with overall calorie intake and level of fitness throughout life. There are those who would debate that, and suggest that the specific dietary components shape gut microbe populations, and those populations have just as significant an effect as exercise over the span of a lifetime. Regardless, eating a calorie restricted diet tends to solve both of those problems, making the debate moot in a practical sense, and no-one is arguing against aerobic fitness as a good thing in life.

From the standpoint of heart health, the Tsimane are a model group. A population indigenous to the Bolivian Amazon, the Tsimane demonstrate next to no heart disease. They have minimal hypertension, low prevalence of obesity, and their cholesterol levels are relatively healthy. And those factors don't seem to change with age. Also minimal is the incidence of type 2 diabetes. Researchers have now conducted the first systematic study that examines what the Tsimane consume on a regular basis and compares it to that of the Moseten, a neighboring population with similar language and ancestry, but whose eating habits and lifeways are more impacted by outside forces.

Using the same measurement strategy employed by the U.S. Centers for Disease Control and Prevention's National Health and Nutrition Examination Survey, the researchers interviewed 1,299 Tsimane and 229 Moseten multiple times about everything they had eaten or drunk in the previous 24 hours. Using published and their own nutritional estimates for all items, and a variety of methods to estimate portion size, they provided a detailed breakdown of daily food intake. The high-calorie (2,433-2,738 kcal/day) Tsimane diet was characterized by high carbohydrate and protein intake, and low fat intake (64, 21 and 15 percent of the diet, respectively). In addition, the Tsimane don't eat a wide variety of foods, relative to the average U.S. or Moseten diet. Almost two-thirds of their calories are derived from complex carbohydrates, particularly plantains and rice. Another 16 percent comes from over 40 species of fish, and 6 percent from wild game. Only 8 percent of the diet came from markets.

Despite the low dietary diversity, the researchers found little evidence of micronutrient deficiencies in the Tsimane's daily intake. Calcium and a few vitamins (D, E and K) were in short supply, but the intake of potassium, magnesium, and selenium - often linked to cardiovascular health - far exceeded U.S. levels. Dietary fiber intake was almost double U.S. and Moseten levels. The conclusion: A high-energy diet rich in complex carbohydrates is associated with low cardiovascular disease risk, at least when coupled with a physically active lifestyle (Tsimane adults average 17,000 or so steps per day, compared to Americans' 5,100). Moving away from a diet that is high in fiber and low in fat, salt, and processed sugar represents a serious health risk for transitioning populations.

The State of Animal Models for the Hallmarks of Aging

The hallmarks of aging paper described a categorization of aging into discrete forms of damage and change, strongly influenced by more than a decade of work to popularize the SENS view of aging as a catalog of forms of molecular damage. The hallmarks are distinct from the SENS categorization, incorporating a number of items that are downstream from the molecular damage that causes aging, but the two overlap to some degree. We might also consider the seven pillars taxonomy of aging, and I'm sure that more similar overviews will arise in the future as various categories start to show promise in the development of therapies to treat aging as a medical condition. The challenge facing the effective use of any such taxonomy of facets of aging is that there are few to no animal models that exhibit just one of those facets, or in which a facet is easily manipulated in isolation of all of the others. Everything in cellular biochemistry connects to everything else.

In this open access paper, researchers review the current state of animal models from a hallmarks of aging perspective, finding it lacking. This is just as true for the SENS view of aging. In both cases, generating animal models that exhibit to at least some degree of physiological levels of only one of the forms of damage will be important. It is also important to understand that models that exhibit far greater than normal levels of damage observed in the usual course of aging may or may not be helpful. This is the situation for lineages with reduced DNA repair activity in the nucleus or mitochondria, where the animals exhibit far greater levels of mutational damage than normally occurs even in late old age. Despite existing for quite some time, these models have not to date resulted in a definitive outcome in the debate over nuclear DNA damage, and it is still the case that using them for studies of aging requires a very careful consideration of the details of the experiment to avoid misleading results.

The use of model organisms in aging research has been essential to achieve a key milestone in the field: the aging process can be modulated. Instead of just a passive, undefined decline of physiological functions, aging has turned out to be the result of a complex interconnection of genetic and biochemical mechanisms that have recently been categorized in 9 molecular hallmarks: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Although we are still far from understanding how this intricate network of pathways inexorably coordinates organismal deterioration, in vivo studies in animal models have proven that single genetic manipulations can extend lifespan or ameliorate certain age-related phenotypes. Also, external interventions, that is, caloric restriction, which target specific pathways, have demonstrated that aging can be delayed in a variety of species.

For several years, the use of invertebrate animal models-such as the worm Caenorhabditis elegans or the fruit-fly Drosophila melanogaster-has led aging research by providing the first insights into those molecular pathways that are determinant in the aging process and for lifespan extension. Despite the great progress achieved by using simple model organisms carrying mutations in specific genes, increasing efforts have been made during recent years to address whether these fundamental mechanisms are also shared by mammalian systems. In this regard, mouse models have become an excellent tool in aging research because of their relative short lifespan (which allows the monitoring of the aging process in a reasonable window frame) and to the feasibility of performing genetic manipulations. Also, mice share many of the age-related phenotypes found in human subjects, including the increased risk to develop certain diseases with age, such as cancer. Nevertheless, those age-related pathologies frequently found in elderly humans and absent in aged mice, such as certain cardiovascular (ie, atherosclerosis) or neurodegenerative (ie, Alzheimer's) diseases, can be studied using the appropriate genetically modified mouse model already created to mimic these common human disorders. Accordingly, in this review, we revisit the hallmarks of aging through the prism of those biological insights provided exclusively by gain- and loss-of-function mouse models.

We have focused on those genetic interventions that have a direct impact on a specific hallmark and discuss how this manipulation affects the aging process. Of note, the pleiotropic function of certain genes together with the inherent interconnection of some hallmarks makes sometimes difficult to point at a single molecular pathway/hallmark once a gene has been deleted or overexpressed. Finally, we have primarily highlighted those genetically engineered mice that shorten or increase healthy lifespan, keeping in mind that certain features of mouse models showing accelerated aging are not present in normal aging and vice versa. We have found examples of existing animal models for the majority of hallmarks of aging. However, this analysis has also surfaced some weaknesses and many challenges ahead.

The First Longevity Leaders Conference will be Held in London in 2019

The business community includes many supporting organizations that host conferences, cultivate professional networks, and analyze markets and businesses. The biotechnology industry is waking up to the potential of treating aging as a medical condition, particularly now that a sizable amount of venture funding is flowing to the development of the first rejuvenation therapies worthy of the name. The groups that run conferences and business networks are starting to play their part, such as LSX Leaders, a life science business network that is putting together the Longevity Leaders conference early next year. We should expect to see more conference series dedicated to this topic launching in the next few years if the present pace of growth keeps up.

The Longevity Leaders Conference is about both the science of longevity and the business of longevity. Its purpose is to connect the thought leaders, key opinion leaders, CEOs, innovators, and disruptors from the world of life sciences, technology, financial services, government and the investment community to discuss how the grand challenges of Longevity can be tackled, how the significant opportunities can be seized, and to forge the partnerships and relationships to succeed in this new age.

The themes in focus include: The future of the science of ageing, accelerating research and development to enable the eradication of age-related disease and cracking the code to treat ageing as a unitary disease. The future of care: what are the new business models and partnerships needed to support assisted living, the care homes of the future, domiciliary care, chronic care management and end of life care? Realising the potential of the longevity industry revolution: what are the business model innovations in research and development, care, consumer and financial services necessary to ensure success? Derisking longevity: how can companies and pension funds derisk from longevity? What are the best new ideas to manage longevity risk? The technology challenge: realising the potential of new connected and digital health possibilities and the power of artificial intelligence and blockchain to enhance and extend human health lifespans. The investment opportunity: how can investors reap the longevity dividend?

Revolutionary new developments in geroscience and biotechnology, the advent of personalised, precision, and preventative medicine and other disruptive technologies are all converging and conspiring to mean that extending lifespan and healthspan beyond 100 years will soon become the norm. There can be no doubt that the age of longevity is upon us, and it is up to us to tackle its grand challenges - from eradicating age-related disease, and perhaps ageing itself, to redefining the future of care, reimagining retirement living, derisking longevity in financial service industries and developing the commercial and business models that will lead to prosperity in this new age. Those who invest and develop the technology, products and solutions to meet these challenge stand to reap incredible dividends of the multi-trillion longevity industry that will disrupt traditional working norms, challenge virtually all businesses and transform society's structure.

Higher Protein Intake Associated with Slower Onset of Disability in Old People

Lower protein intake is suspected of being a contributing cause of a number of age-related conditions, such as sarcopenia, the loss of muscle mass and strength. Researchers here find an association between lower protein intake and a faster pace of decline with age, but it is easy to argue over the direction of causation. After all, older people may eat less protein because of a metabolism that offers hunger prompts less frequently, or because of age-related conditions that make eating more of a challenge. The degeneration may be the cause rather than the result.

To live successfully and independently, older adults need to be able to manage two different levels of life skills: basic daily care and basic housekeeping activities. People 85-years-old and older form the fastest-growing age group in our society and are at higher risk for becoming less able to perform these life skills. For this reason, researchers are seeking ways to help older adults stay independent for longer. Recently, a research team focused their attention on learning whether eating more protein could contribute to helping people maintain independence.

Protein is known to slow the loss of muscle mass. Having enough muscle mass can help preserve the ability to perform daily activities and prevent disability. Older adults tend to have a lower protein intake than younger adults due to poorer health, reduced physical activity, and changes in the mouth and teeth. To learn more about protein intake and disability in older adults, the research team used data from the Newcastle 85+ Study. This study's researchers approached all people turning 85 in 2006 in two cities in the UK for participation. At the beginning of the study in 2006-2007, there were 722 participants, 60 percent of whom were women. The participants provided researchers with information about what they ate every day, their body weight and height measurements, their overall health assessment (including any level of disability), and their medical records.

The researchers learned that more than one-quarter (28 percent) of very old adults had protein intakes below the recommended dietary allowance. The researchers noted that older adults who have more chronic health conditions may also have different protein requirements. To learn more about the health benefits of adequate protein intake in older adults, the researchers examined the impact of protein intake on the increase of disability over five years. The researchers' theory was that eating more protein would be associated with slower disability development in very old adults, depending on their muscle mass and muscle strength. As it turned out, they were correct. Participants who ate more protein at the beginning of the study were less likely to become disabled when compared to people who ate less protein.

Calorie Restriction Slows Loss of Gut Integrity with Age

In flies, the declining state of the intestine is a critical aspect of aging, the strongest determinant of mortality. This central position of the intestine in aging is not the case in mammals, but loss of integrity of the intestinal wall is still a major driver of chronic inflammation. That inflammation in turn accelerates progression of all of the common age-related diseases; it is a major aspect of aging, and control of inflammation is a goal well worth chasing. The practice of calorie restriction has been shown to slow down near all measurable aspects of aging, and the aging of the intestinal wall is no exception, as researchers demonstrate here. The noteworthy aspect of this research is the demonstration that the microbes of the gut do not seem to be all that involved in the pace of decline, which is not what one might expect based on recent years of work on the role of the gut microbiome in aging.

Flies eating a Spartan diet are protected from leaky gut and the systemic inflammation associated with it as they age. Conversely, flies on a rich diet are more prone to developing intestinal permeability, a condition linked to a variety of human conditions including inflammatory bowel disease. Researchers have shown that gaps in the intestinal barrier are caused by an age-related increase in the death of intestinal epithelial cells, also known as enterocytes.

The researchers zeroed in on dMyc, a gene involved in cell proliferation. They observed that levels of dMyc act as a barometer of cellular fitness in enterocytes, post-mitotic intestinal cells. They found that cells that have too little dMyc get eliminated by neighboring cells through a process termed cell competition in an attempt to maintain gut health. Levels of dMyc naturally decline with age in enterocytes, leading to excessive cell loss and thus a leaky gut. This decline in dMyc was enhanced by a rich diet, while dietary restriction maintained dMyc level in the flies, preventing leaky gut and extending the lifespan of the animals.

The researchers also looked at the role of dysbiosis, an imbalance in the intestinal bacteria or microbiome of the flies, as a potential contributor to leaky gut. Even though dysbiosis has been proposed as a leading cause of leaky gut, researchers found that removing intestinal bacteria with antibiotics conferred only minimal protection to the animals and did not prevent age-related damage to enterocytes. "The intestinal epithelium is affected by everything that moves through the gut. It would make sense that diet would have major impact on the health of those cells, especially over a lifetime of eating. While we understand the interest in the role of the microbiome, we think that diet may ultimately be the primary driver in cellular changes leading to leaky gut."

Fibroblasts in Old Skin Lose their Functional Identity

Researchers here describe the character of fibroblasts in old skin as a loss of characteristic function and identity. The fibroblasts begin to take on aspects of other cell types, and thus the character of skin changes for the worse. In the publicity materials this decline in cell function is described as a cause of aging, but that should probably be taken to mean that the researchers consider it a contributing cause to age-related pathology rather than a root cause of aging per se. Dysfunction of this nature has all the signs of being a downstream consequence in aging, cellular misbehavior that is a reaction to earlier processes, such as the accumulation of molecular damage within and between cells, or the changes in cell signaling that results from that damage.

With age, our tissues lose their function and capacity to regenerate after being damaged. The main conclusion drawn from recent findings is that these fibroblasts lose their cell identity, as if they had "forgotten" what they are, and consequently their activity is altered, thus affecting tissue. The new study reveals the cellular and molecular pathways affected by ageing and proposes that they could be manipulated to delay or even reverse the skin ageing process.

Dermal fibroblasts are key for the production of collagen and other proteins that make up the dermis and that preserve the skin's function as a barrier. The activity of these cells is also crucial for the repair of skin damage. As we age, the dermis loses its capacity to produce collagen, and consequently its capacity to repair wounds is also significantly impaired. A single-cell analysis confirmed the loss of fibroblast identity in aged animals. Using sophisticated computational tools, scientists observed that aged fibroblasts show a less defined molecular conformation compared to young fibroblasts and come to resemble the undefined cell states observed in newborn animals.

"The elderly face many problems in this regard because their skin does not heal properly and its barrier properties are decreased, thus increasing the risk of skin infections and systemic infections. The notion that the loss of cell identity is one of the underlying causes of ageing is interesting and one that we believe hasn't been considered before."


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