Fight Aging! Newsletter, August 29th 2016

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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  • Mapping the Role of Foxn1 in Thymic Function
  • An Interview with Kelsey Moody of Ichor Therapeutics, Bringing a SENS Therapy for Macular Degeneration to the Clinic
  • Criticizing Programmed Theories of Aging
  • A Small Selection of Recent Research on Lifestyle Choices and Aging
  • Increased Levels of Neuregulin-1 Reduce Amyloid Plaques and Improve Memory in a Mouse Model of Alzheimer's Disease
  • Latest Headlines from Fight Aging!
    • Towards a Regenerative Therapy for the Lacrimal Gland and Dry Eyes
    • Development of a Cell Therapy to Increase Remyelination in the Brain
    • Enhancing Cell Therapy to Enable Greater Recovery Following Stroke
    • Cells can Transfer Lysosomes, Spreading Damaging Age-Related Waste Materials
    • Shorter Period of Rapamycin Treatment in Mice Produces Greater Slowing of Aging
    • Ghrelin Receptor and Inflammaging
    • Marmosets in Aging Research
    • A Scanning Approach to Detect Transthyretin Amyloid Buildup in the Heart
    • A Potential Way to Speed the Recovery Phase of an Immune System Reboot
    • A Bleak Outlook on Aging

Mapping the Role of Foxn1 in Thymic Function

Researchers have of late been mapping the activities and relationships of Forkhead box protein N1 (Foxn1) in the thymus, and the paper I'll point out today outlines some of the most recent findings. Sadly it isn't open access, but I'm sure that won't stop the determined reader in this day and age. This work is of interest to our community of longevity science supporters because increased levels of Foxn1 have been shown to restore a more youthful level of thymic activity in older animals and human cell lines, and have been used to regrow thymic tissue when used in conjunction with cell therapies.

Why is thymic activity important? To simplify greatly, the thymus is where new T cells of the adaptive immune system mature after they are created. Its comparatively low level of activity in adults is one of the gating factors limiting the supply of new immune cells across most of the life span. Children have a very active thymus, and as a result a comparatively large supply of new immune cells, but the organ atrophies quite early in adulthood in a process known as thymic involution. Fat tissue replaces most of the structures that once nurtured immune cells and going forward an adult must get by with far fewer new immune cells. This low level of supply is one of the factors that effectively limits the size of the immune cell population in adults, and the fact that this population is limited eventually gives rise to a form of harmful resource misallocation. After a lifetime of exposure to pathogens, by the time old age arrives too many immune cells become focused on threats that cannot be cleared from the body, such as cytomegalovirus. When a large fraction of the limited population of cells become uselessly specialized in that way, too few cells are left to perform all of the other needed tasks: destroying cancerous and senescent cells, tackling unfamiliar pathogens, and so on.

The decline of the immune system is an important component of the frailty of aging, but this isn't just because old people become very vulnerable to infection. A failing immune system accelerates many of the other causes of aging. It produces greater chronic inflammation, as it is more active even as it is less able to do its job, contributing to a faster progression of near all of the common age-related diseases. The immune system is responsible for destroying senescent cells, which in larger numbers cause harm through the creation of inflammation and destruction of tissue structures. Fewer of these cells destroyed means more left to produce damage and dysfunction. Then there are potentially and actually cancerous cells, which have a greater chance of survival as the immune system becomes ever less effective. This is not to mention that the immune system plays a role in wound healing, as well as many other important processes. Given all of this, the goal of a restored immune system is a very important one, and even partially restoration should produce clear benefits.

One approach to this problem is to destroy the unwanted cells that are taking up space. Another approach is to deliver a much larger supply of new immune cells, such as directly via regular cell therapies, or alternatively through restoration of the thymus. There are a few different possible ways to restore the thymus. Transplantation has been shown to work in mice, producing improved immune function and extension of life, but that isn't going to work in human medicine since we'd want everyone to get a new thymus in old age. Tissue engineering is a strong possibility: researchers have made promising inroads towards the creation of thymic tissue. Then there is the use of Foxn1 to spur regrowth of the thymus, and this can even be mixed in with forms of cell therapy to grow thymic tissue within the patient rather than build outside the body and then transplant. Given the demonstrated importance of Foxn1, it is worth paying attention to research such the results noted here.

Study suggests routes to improved immunity in older people

Humans, like all higher animals, use T cells as part of the immune system, to fight off infections and cancer. T cells are generated in an organ called the thymus, where they closely interact with thymic epithelial cells (TEC) as they mature. People without TEC cannot generate T cells, severely compromising the immune system and consequently increasing the risk for life threatening infections and cancer. More than 20 years ago the transcription factor Foxn1 was identified as an essential molecule for the normal development of TEC. However, the genes directly controlled by Foxn1 - and thus responsible for the various TEC functions - have remained unidentified.

The researchers used new experimental models and analytical tools to investigate which genes were regulated by Foxn1 and how it affected them. Transcription factors bind to particular sections of our DNA and the team is the first to identify the DNA sequence bound by Foxn1. From there, they identified the hundreds of genes whose expression is regulated by this master regulator. These include genes that are essential to attract precursor cells in the blood, which are destined to become T-cells, to the thymus, genes that commit these precursor cells to become T cells and genes that provide the molecular machinery which allows the selection of those T cells that best serve an individual. Experiments in which Foxn1 expression by TEC was inhibited, confirmed that the transcription factor needs to be continuously present for TEC to function normally.

"The thymus is the organ in humans that first displays an age-dependent, physiological decline in function. It grows until puberty and then shrinks throughout the rest of our lives. This is thought to contribute to the decline in immunity in older people, which makes them more susceptible to opportunistic infections and cancers. The findings from these studies therefore provide important insight into the genetic control of regular TEC function and identify new potential strategies to preserve thymus function for longer, raising the prospect of a healthier old age."

Foxn1 regulates key target genes essential for T cell development in postnatal thymic epithelial cells

Thymic epithelial cell differentiation, growth and function depend on the expression of the transcription factor Foxn1; however, its target genes have never been physically identified. Using static and inducible genetic model systems and chromatin studies, we developed a genome-wide map of direct Foxn1 target genes for the postnatal thymic epithelium and defined the Foxn1 binding motif. We determined the function of Foxn1 in these cells and found that, in addition to the transcriptional control of genes involved in the attraction and lineage commitment of T cell precursors, Foxn1 regulates the expression of genes involved in antigen processing and thymocyte selection. Thus, critical events in thymic lympho-stromal cross-talk and T cell selection are indispensably choreographed by Foxn1.

An Interview with Kelsey Moody of Ichor Therapeutics, Bringing a SENS Therapy for Macular Degeneration to the Clinic

As I mentioned last week, earlier this year Fight Aging! invested a modest amount in the Ichor Therapeutics initiative to develop a treatment for macular degeneration, joining a number of other amateur and professional investors in helping to get this venture started. The approach taken here is based on the results of research carried out at the Methuselah Foundation and SENS Research Foundation over much of the past decade, funded by philanthropists and the support of our community of longevity science enthusiasts. This is how we succeed in building the future: medical science in the laboratory leads to medical development in startup companies, each new stage bringing treatments capable of repairing specific forms of age-related molecular damage that much closer to the clinic.

Ichor Therapeutics is one of a growing number of success stories to emerge from the SENS rejuvenation research community. Young scientists, advocates, and donors involved in earlier projects - years ago now - have gone on to build their own ventures, while retaining an interest in stepping up to do something meaningful to help bring an end to aging. Back in 2010, Kelsey Moody worked on the LysoSENS project to find ways to break down damaging metabolic waste in old tissues; fast-forward six years, and he is the now the CEO of a successful small biotechnology company with a great team, taking that very same technology and putting it to good use. I recently had the chance to ask Kelsey a few questions about the future of SENS rejuvenation research, as well as how the Ichor scientists intend to construct a new class of therapy for macular degeneration, one based on removing one of the root causes of the condition.

Who are the people behind Ichor Therapeutics? How did you meet and decide that this was the thing to do? Why macular degeneration as a target?

People have always been the focus of Ichor. Since day one we have worked to create a positive environment that cultivates a product-oriented research focus and emphasizes autonomy and personal accountability for work. As a result, ambitious self-starters tend to find their way to Ichor and remain here. However, we recognized early on that just filling a lab with a bunch of blue-eyed bushy tailed young up-and-comers is not sufficient to develop a robust, mature, translational pipeline. We have augmented our team with a number of critical staff members who are seasoned pharma operators, including our Quality Assurance Director and General Counsel.

Age-related macular degeneration (AMD) was chosen as a target because we believe it is the closest SENS therapy to the clinic. While we obviously have an interest in providing cures for the patients suffering from AMD and are attracted to the large market opportunities such a treatment could bring, our broader interest is in validating the entire SENS paradigm. We believe that Aubrey de Grey continues to receive excessive criticism because nothing spun out of SENS has ever made it into a legitimate pre-clinical pipeline, much less to the bedside. However, this does not mean he is wrong. Our goal is to be the first group to bring a SENS inspired therapy into the clinic and in doing so, silence critics and generate new energy and capital for this cause.

I understand there's a lengthy origin story for the approach you are taking to treat AMD; it'd be great to hear some of it.

Our approach to treating AMD is based on the hypothesis that cellular junk that accumulates over the lifespan significantly contributes to the onset and progression of AMD. Our goal is to periodically reduce the burden of the junk so it never accumulates to levels sufficient to induce pathology. The strategy to accomplish this calls for the identification of enzymes that can break down the junk in a physiological setting, and the engineering of these enzymes such that they can break down the target in the correct organelle of the correct cell without appreciable collateral damage to healthy cells or tissue.

Methuselah Foundation and SENS Research Foundation did excellent work in establishing this program nearly a decade ago. They successfully identified a number of candidate enzymes that could break down the molecular junk, but reported that the targeting systems evaluated failed to deliver these enzymes to the appropriate organelles and cells. My group reevaluated these findings, and discovered that these findings were flawed. The delivery failure could be entirely attributed to a subtle, yet highly significant difference between how the target cells behave outside of the body as compared to inside the body. It turned out that the approach was in fact valid, it was the cell based assay that had been used that was flawed. This discovery was striking enough that SENS Research Foundation provided Ichor with funding and a material and technology transfer agreement to reassess the technology, and over 700,000 in directed program investments and grants have been received in the last year or two.

You recently completed a round of funding for the AMD work; what is the plan for the next year or so?

The new funds will allow us to develop a portfolio of enzyme therapy candidates to treat AMD. We will obtain critical data necessary to secure follow-on investment including in vitro studies (cell culture studies to confirm mechanism of action and cytotoxicity) and pivotal proof-of-concept in vivo studies, such as toxicity, PK/PD (how long the enzyme stays in the body and where), and efficacy. We will also be restructuring the company (reincorporating an IP holding company in Delaware, ensuring all contracts are up to date and audited) and ensuring our IP position is on solid footing (licensing in several related patents from existing collaborators, and filing several provisional patents from our intramural work). Collectively, we believe these efforts will position us to obtain series A for investigational new drug (IND) enabling pre-clinical studies.

You've been involved in the rejuvenation research community for quite some time now. What is your take on the bigger picture of SENS and the goal of ending aging?

This is a loaded question. What I can say is that the medical establishment has made great progress in the treatment of infectious disease through the development of antibiotics, vaccines, and hygiene programs. However, similar progress has not been realized for the diseases of old age, despite exorbitant expenditures. I have chosen to work in this space because I think a different approach is necessary, and it is here that I believe my companies and I can be the most impactful. I think SENS provides a good framework within which to ask and answer questions.

What do you see as the best approach to getting nascent SENS technologies like this one out of the laboratory and into the clinic?

We need more people who fully understand, in a highly detailed way, what a real translational path looks like. To take on projects like this, being a good scientist is not enough. We need people who can speak business, science, medicine, and legal, and apply these diverse disciplines to a well articulated, focused product or problem. There is no shortage of people who partially understand some of these, but the details are not somewhat important - they are all that matter for success in this space.

Another area is for investors. Some of the projects that come across my desk for review are truly abysmal, yet I have seen projects that are clearly elaborate hoaxes or outright scams (to anyone who has stepped foot in a laboratory) get funded to the tune of hundreds of thousands or more. While it is perfectly reasonable for high net worth individuals to gamble on moon shots in the anti-aging space (and I am ever grateful for the investors who have taken such a gamble on us) even aggressive development strategies should have some basis in reality. This is especially true as more and more high tech and internet investors move into the space.

If this works stupendously well, what comes next for Ichor Therapeutics?

I really want to get back into stem cell research, but I basically need a blank check and a strong knowledge of the regulatory path to clinic before I feel comfortable moving into the space. A successful AMD exit would accomplish both of these goals, and position us to pivot to cell-based therapies.

Criticizing Programmed Theories of Aging

Today I'll point out an open access critique of programmed aging theories by the originator of the disposable soma theory of aging, one of the modern views of aging as accumulated damage rather than programming. The question of how and why we age is wrapped in a lot of competing theory, but of great practical importance. Our biochemistry is enormously complex and incompletely mapped, and thus the processes of aging, which is to how exactly our biochemistry changes over time, and all of the relationships that drive that change, are also enormously complex and incompletely mapped. Nonetheless, there are shortcuts that can be taken in the face of ignorance: the fundamental differences between young and old tissue are in fact well cataloged, and thus we can attempt to reverse aging by treating these changes as damage and repairing them. If you've read through the SENS rejuvenation research proposals, well, that is the list. The research community may not yet be able to explain and model how exactly this damage progresses, interacts, and spreads from moment to moment, but that effort isn't necessary to build repair therapies capable of rejuvenation. You don't need to build a full model of the way in which paint cracks and peels in order to scrub down and repaint a wall, and building that model is a lot most costly than just forging ahead with the painting equipment.

The engineering point of view described above, simply getting on with the job when there is a good expectation of success, is somewhat antithetical to the ethos and culture of the sciences, which instead guides researchers to the primary goal of obtaining full understanding of the systems they study. In practice, of course, every practical application of the life sciences is created in a state of partial ignorance, but the majority of research groups are nonetheless oriented towards improving the grand map of the biochemistry of metabolism and aging rather than doing what can be done today to create rejuvenation therapies. Knowledge over action. If we had all the time in the world this would be a fine and golden ideal. Unfortunately we do not, which places somewhat more weight on making material progress towards the effective treatment of aging as a medical condition - ideally by repairing its causes.

But what are the causes of aging? The majority view in the research community is that aging is a process of damage accumulation. The normal operation of metabolism produces forms of molecular damage in cells and tissues, a sort of biological wear and tear - though of course the concept of wear and tear is somewhat more nuanced and complex in a self-repairing system. This damage includes such things as resilient cross-links that alter the structural properties of the extracellular matrix and toxic metabolic waste that clutters and harms long-lived cells. As damage accumulates, our cells respond in ways that are a mix of helpful and harmful, secondary and later changes that grow into a long chain of consequences and a dysfunctional metabolism that is a long way removed from the well-cataloged fundamental differences between old and young tissues. An old body is a complicated mess of interacting downstream problems. In recent years, however, a growing minority have suggested and theorized that aging is not caused by damage, but is rather a programmed phenomenon - that some portion of the what I just described as the chain of consequences, in particular epigenetic changes, are in fact the root cause of aging. In the programmed view of aging, epigenetic change causes dysfunction and damage, not the other way around. That these two entirely opposite views can exist is only possible because there is no good map of the detailed progression of aging - only disconnected snapshots and puzzle pieces. There is a lot of room to arrange the pieces in any way that can't be immediately refuted on the basis of well-known past studies.

There are two ways to settle the debate of aging as damage versus aging as evolved program. The first is to produce that grand map of metabolism and aging, something that I suspect is at the least decades and major advances in life science automation removed from where we stand now. The other is to build therapies that produce large degrees of rejuvenation, enough of a difference to put it far beyond argument that the approach taken is the right one. That is not so far away, I believe, as the first SENS rejuvenation therapies are presently in the early stages of commercial development. I think that, even with the comparative lack of funding for this line of development, ten to twenty years from now the question will be settled beyond reasonable doubt. Meanwhile, the programmed aging faction has become large enough and their positions coherent enough that the mainstream is beginning to respond substantially to their positions; I expect that this sort of debate will continue all the way up to and well past the advent of the first meaningful rejuvenation therapies, which at this point look to be some form of senescent cell clearance.

Can aging be programmed? A critical literature review

Many people, coming new to the question of why and how aging occurs, are attracted naturally to the idea of a genetic programme. Aging is necessary, it is suggested, either as a means to prevent overcrowding of the species' environment or to promote evolutionary change by accelerating the turnover of generations. Instead of programmed aging, however, the explanation for why aging occurs is thought to be found among three ideas all based on the principle that within iteroparous species (those that reproduce repeatedly, as opposed to semelparous species, where reproduction occurs in a single bout soon followed by death), the force of natural selection declines throughout the adult lifespan. This decline occurs because at progressively older ages, the fraction of the total expected reproductive output that remains in future, on which selection can act to discriminate between fitter and less-fit genotypes, becomes progressively smaller. Natural selection generally favours the elimination of deleterious genes, but if its force is weakened by age, and because fresh mutations are continuously generated, a mutation-selection balance results. The antagonistic pleiotropy theory suggests that a gene that has a benefit early in life, but is detrimental at later stages of the lifespan, can overall have a net positive effect and will be actively selected. The disposable soma theory is concerned with optimizing the allocation of resources between maintenance on the one hand and other processes such as growth and reproduction on the other hand. An organism that invests a larger fraction of its energy budget in preventing accumulation of damage to its proteins, cells and organs will have a slower rate of aging, but it will also have fewer resources available for growth and reproduction, and vice versa. Mathematical models of this concept show that the optimal investment in maintenance (which maximizes fitness) is always below the fraction that is necessary to prevent aging.

In recent years, there have been a number of publications claiming that the aging process is a genetically programmed trait that has some form of benefit in its own right. If this view were correct, it would be possible experimentally to identify the responsible genes and inhibit or block their action. This idea is, however, diametrically opposed to the mainstream view that aging has no benefit by its own and is therefore not genetically programmed. Because experimental strategies to understand and manipulate the aging process are strongly influenced by which of the two opinions is correct, we have undertaken here a comprehensive analysis of the specific proposals of programmed aging. On the principle that any challenge to the current orthodoxy should be taken seriously, our intention has been to see just how far the various hypotheses could go in building a convincing case for programmed aging.

This debate is not only of theoretical interest but has practical implications for the types of experiments that are performed to examine the mechanistic basis of aging. If there is a genetic programme for aging, there would be genes with the specific function to impair the functioning of the organism, that is to make it old. Under those circumstances, experiments could be designed to identify and inhibit these genes, and hence to modify or even abolish the aging process. However, if aging is nonprogrammed, the situation would be different; the search for genes that actively cause aging would be a waste of effort and it would be too easy to misinterpret the changes in gene expression that occur with aging as primary drivers of the senescent phenotype rather than secondary responses (e.g. responses to molecular and cellular defects). It is evident, of course, that genes influence longevity, but the nature of the relevant genes will be very different according to whether aging is itself programmed or not.

For various programmed theories of aging, we re-implemented computational models, developed new computational models, and analysed mathematical equations. The results fall into three classes. Either the ideas did not work because they are mathematically or conceptually wrong, or programmed death did evolve in the models but only because it granted individuals the ability to move, or programmed death did evolve because it shortened the generation time and thus accelerated the spread of beneficial mutations. The last case is the most interesting, but it is, nevertheless, flawed. It only works if an unrealistically fast-changing environment or an unrealistically high number of beneficial mutations are assumed. Furthermore and most importantly, it only works for an asexual mode of reproduction. If sexual reproduction is introduced into the models, the idea that programmed aging speeds up the spread of advantageous mutations by shortening the generation time does not work at all. The reason is that sexual reproduction enables the generation of offspring that combine the nonaging genotype of one parent with the beneficial mutation(s) found in the other parent. The presence of such 'cheater' offspring does not allow the evolution of agents with programmed aging.

In summary, all of the studied proposals for the evolution of programmed aging are flawed. Indeed, an even stronger objection to the idea that aging is driven by a genetic programme is the empirical fact that among the many thousands of individual animals that have been subjected to mutational screens in the search for genes that confer increased lifespan, none has yet been found that abolishes aging altogether. If such aging genes existed as would be implied by programmed aging, they would be susceptible to inactivation by mutation. This strengthens the case to put the emphasis firmly on the logically valid explanations for the evolution of aging based on the declining force of natural selection with chronological age, as recognized more than 60 years ago. The three nonprogrammed theories that are based on this insight (mutation accumulation, antagonistic pleiotropy, and disposable soma) are not mutually exclusive. There is much yet to be understood about the details of why and how the diverse life histories of extant species have evolved, and there are plenty of theoretical and experimental challenges to be met. As we observed earlier, there is a natural attraction to the idea that aging is programmed, because developmental programming underpins so much else in life. Yet aging truly is different from development, even though developmental factors can influence the trajectory of events that play out during the aging process. To interpret the full complexity of the molecular regulation of aging via the nonprogrammed theories of its evolution may be difficult, but to do it using demonstrably flawed concepts of programmed aging will be impossible.

Given that the author here has in the past been among those who dismissed the SENS initiative as an approach to treating aging by repairing damage, it is perhaps a little amusing to see him putting forward points such as this one: "despite the cogent arguments that aging is not programmed, efforts continue to be made to establish the case for programmed aging, with apparent backing from quantitative models. It is important to take such claims seriously, because challenge to the existing orthodoxy is the path by which science often makes progress." Where was this version of the fellow ten years ago?

A Small Selection of Recent Research on Lifestyle Choices and Aging

Today I'll point out a recent selection of studies on lifestyle choices and life expectancy: the costs of bad choices and the benefits of good choices. The numbers are not particular new, but it is good to be occasionally reminded of the bounds of the possible when it comes to choice versus technology. It is impossible to reliably live to 100 through the use of exercise, diet, and other good lifestyle choices. The best you can do is to change your odds from being low to being slightly less low. Lifestyle choices are not the primary driver of your future longevity. According to the actuarial community, the chance of living to 100 is 10-15% for people in the middle of life now, as opposed to 1% or so for people born a century ago. This difference is due to the progress in every area of medical technology that has produced 150 years of a gentle upward slope in adult life expectancy. If projecting that trend outwards for the rest of our lives at the same steady pace one arrives at these odds. This is the primary business of actuaries, to provide these conservative models of the future.

It is highly unlikely that this trend will in fact continue at the same pace, however, and actuaries have increasingly hedged their pronouncements for more than a decade now. Everything accomplished to date in the extension of human life expectancy has been an incidental byproduct, a side-effect of initiatives that did not deliberately target or address the root causes of aging. Aging is a consequence of cell and tissue damage and we are in the midst of a transition towards research and therapies that can slow or repair this damage; treating aging as a medical condition and working deliberately to bring it under control, in other words. The different between the past and the future of aging will be the difference between a problem left to run untended and a problem that people are actively trying to fix. The trend in life expectancy will leap to the upside in decades ahead.

The evidence suggests that the range in human life expectancy that is under our control through common lifestyle choices is somewhere in the vicinity of fifteen to twenty years. An exemplary set of choices might add five to ten years to life expectancy, and a truly terrible set of choices loses five to ten years from the baseline average. Why does this matter, beyond the obvious? It matters because we live in an age of revolutionary, rapid progress in biotechnology, through the present state of regulation ensures that what happens in the laboratory is only slowly making it to the clinic. Despite the regulatory ball and chain, a few years of life might one day make the difference between being able to benefit from a new rejuvenation therapy, and thus gaining health and additional years, or dying too soon. Ahead of us is the upward curve of technology versus the downward curve of individual mortality. Some people will reach the point at which medical technology keeps them alive and in good health for long enough to reach the era of agelessness, when aging can be completely controlled through comprehensive periodic repair of molecular damage. This is the primary reason as to why it is worth living a better lifestyle rather than a worse lifestyle - quite aside from the other benefits, such as a longer life, better health, lower lifetime medical expenditure, and so on.

Diet and exercise can reduce protein build-ups linked to Alzheimer's

In the study, 44 adults ranging in age from 40 to 85 (mean age: 62.6) with mild memory changes but no dementia underwent an experimental type of PET scan to measure the level of plaque and tangles in the brain. Researchers also collected information on participants' body mass index, levels of physical activity, diet and other lifestyle factors. Plaque, deposits of a toxic protein called beta-amyloid in the spaces between nerve cells in the brain; and tangles, knotted threads of the tau protein found within brain cells, are considered the key indicators of Alzheimer's. The study found that each one of several lifestyle factors - a healthy body mass index, physical activity and a Mediterranean diet - were linked to lower levels of plaques and tangles on the brain scans. Earlier studies have linked a healthy lifestyle to delays in the onset of Alzheimer's. However, the new study is the first to demonstrate how lifestyle factors directly influence abnormal proteins in people with subtle memory loss who have not yet been diagnosed with dementia. Healthy lifestyle factors also have been shown to be related to reduced shrinking of the brain and lower rates of atrophy in people with Alzheimer's.

Diet, Exercise, Both: All Work Equally to Protect Heart Health

Researchers divided 52 overweight, middle-aged men and women into three groups - those who dieted, exercised or did both - and charged them with losing about 7 percent of their body weight during a 12-14 week period. Those who exclusively dieted or exercised were told to decrease their food intake by 20 percent or increase their activity levels by 20 percent. Those who did both were told to eat 10 percent less and move 10 percent more. The researchers analyzed how the changes affected indicators of cardiovascular health, such as blood pressure, heart rate and other markers for heart disease and stroke, like high "bad" cholesterol levels. They found the three strategies were equally effective in improving cardiovascular health, and were expected to reduce a person's lifetime risk of developing cardiovascular disease 10 percent - from 46 percent to 36 percent.

"Because our previous research and that of others indicates that exercise and diet each provide their own unique health benefits beyond those that were evaluated in the current study, it is important to recognize that both diet and exercise are important for health and longevity. While our study did not find additive benefits of calorie restriction and exercise on traditional risk factors for cardiovascular disease, much of the actual risk of developing cardiovascular disease cannot be accounted for by traditional risk factors. Therefore, our findings don't preclude the possibility that dieting and exercise have additive effects for reducing the likelihood of developing cardiovascular disease. Furthermore, an inactive lifestyle itself is a risk factor for cardiovascular disease, although the physiologic mechanisms for this effect are unknown."

Lifestyle Modifications Versus Antihypertensive Medications in Reducing Cardiovascular Events in an Aging Society: A Success Rate-oriented Simulation

It is difficult to compare directly the practical effects of lifestyle modifications and antihypertensive medications on reducing cardiovascular disease (CVD). The purpose of this study was to compare the hypothetical potential of lifestyle modifications with that of antihypertensive medications in reducing CVD in an aging society using a success rate-oriented simulation. We constructed a simulation model for virtual Japanese subpopulations according to sex and age at 10-year intervals from 40 years of age as an example of an aging society. The fractional incidence rate of CVD was calculated as the product of the incidence rate at each systolic blood pressure (SBP) level and the proportion of the SBP frequency distribution in the fractional subpopulations of each SBP. If we consider the effects of lifestyle modifications on metabolic factors and transfer them onto SBP, the reductions in the total incidence rate of CVD were competitive between lifestyle modifications and antihypertensive medications in realistic scenarios. In middle-aged women, the preventive effects of both approaches were limited due to a low incidence rate. In middle-aged men and extremely elderly subjects whose adherence to antihypertensive medications is predicted to be low, lifestyle modifications could be an alternative choice.

Unhealthy habits cost Canadians 6 years of life

Unhealthy habits are costing Canadians an estimated six years of life. Researchers found that smoking, poor diet, physical inactivity, and unhealthy alcohol consumption contribute to about 50 percent of deaths in Canada. The study found: 26 per cent of all deaths are attributable to smoking; 24 per cent of all deaths are attributable to physical inactivity; 12 per cent of all deaths are attributable to poor diet; 0.4 per cent of all deaths are attributable to unhealthy alcohol consumption. For men, smoking was the top risk factor, representing a loss of 3.1 years. For women it was lack of physical activity, representing a loss of 3 years. The researchers also found that Canadians who followed recommended healthy behaviours had a life expectancy 17.9 years greater than individuals with the unhealthiest behaviours.

Increased Levels of Neuregulin-1 Reduce Amyloid Plaques and Improve Memory in a Mouse Model of Alzheimer's Disease

Researchers have recently demonstrated that raised levels of neuroregulin-1 in parts of the brain can reduce the build up of amyloid plaque and improve measures of memory in a mouse lineage engineered to reproduce the features of Alzheimer's disease. This is one of a range of methods that have shown improvements of one kind or another in a mouse model of Alzheimer's disease, and so far most have not exhibited useful results in human studies, or otherwise failed to make it much further along the path to the clinic. The degree to which particular models steer research in a useful direction is a legitimate question: Alzheimer's research is a field in which a great deal of debate, theorizing, and second guessing takes place precisely because meaningful results have yet to emerge from many years of large-scale investment. Given the history it is entirely appropriate to take a wait and see approach to this sort of thing. The reason I point out this research rather than any other is because it involves neuregulin-1.

If you wander the literature, or even just look back in the Fight Aging! archives, you'll find neuregulin-1 showing up in all sorts of interesting lines of research. Levels of neuregulin-1 are high in long-lived naked mole-rats and appear to vary by longevity in various rodent species. Increased neuregulin-1 in the heart has been shown to spur usually active regeneration, and bear in mind that the heart is an organ that normally regenerates poorly following damage in mammalian species. There are clinical trials at various stages for the use of neuregulin in heart failure patients. Higher levels of neuregulin-1 appear to slow kidney damage and might help with nerve repair as well. There are also lines of research that connect neuregulin-1 with exercise levels, making it yet another candidate for one of the myriad ways in which exercise produces health benefits, and others that link neuregulin-1 and related proteins with the exceptional regenerative capacity of species like salamanders and zebrafish. All in all this protein is something of a nexus for numerous distinct areas of research into regeneration and the effects of aging. That said, given all the other information, it is still perhaps a little surprising from an outside observer's perspective to find it reducing levels of amyloid - it doesn't quite follow the theme established above.

Elevating brain protein allays symptoms of Alzheimer's and improves memory

Boosting levels of a specific protein in the brain alleviates hallmark features of Alzheimer's disease in a mouse model of the disorder. The protein, called neuregulin-1, has many forms and functions across the brain and is already a potential target for brain disorders such as Parkinson's disease, amyotrophic lateral sclerosis and schizophrenia. Previously, researchers have shown that treating cells with neuregulin-1, for example, dampens levels of amyloid precursor protein, a molecule that generates amyloid beta, which aggregate and form plaques in the brains of Alzheimer's patients. Other studies suggest that neuregulin-1 could protect neurons from damage caused by blockage of blood flow.

In the new study, researchers tested this idea in a mouse model of Alzheimer's disease by raising the levels of one of two forms of neuregulin-1 in the hippocampus, an area of the brain responsible for learning and memory. Both forms of the protein seemed to improve performance on a test of spatial memory in the models. What's more, the levels of cellular markers of disease - including the levels of amyloid beta and plaques - were noticeably lower in mice with more neuregulin-1 compared to controls. The group's experiments suggest that neuregulin-1 breaks up plaques by raising levels of an enzyme called neprilysin, shown to degrade amyloid-beta. But that is probably not the only route through which neuregulin-1 confers its benefits, and the group is exploring other possible mechanisms - such as whether the protein improves signaling between neurons, which is impaired in Alzheimer's.

A neuregulin-1 treatment is not available on the market, though it is being explored in clinical trials as a potential treatment for chronic heart failure and Parkinson's disease. One advantage of neuregulin-1 as a potential drug is that it can cross the blood brain barrier, which means that it could be administered relatively noninvasively even though the efficiency is not clear. On the other hand, other research suggests too much of the protein impairs brain function. The team has come up with a small molecule that can raise levels of existing neuregulin-1 (rather than administering it directly) and are testing it in cells. This alternative therapy could be a better way to prevent plaques from forming because small molecules more readily cross the blood brain barrier.

Neuregulin 1 improves cognitive deficits and neuropathology in an Alzheimer's disease model

Several lines of evidence suggest that neuregulin 1 (NRG1) signaling may influence cognitive function and neuropathology in Alzheimer's disease (AD). To test this possibility, full-length type I or type III NRG1 was overexpressed via lentiviral vectors in the hippocampus of line 41 AD mouse. Both type I and type III NRG1 improves deficits in the Morris water-maze behavioral task. Neuropathology was also significantly ameliorated. Decreased expression of the neuronal marker MAP2 and synaptic markers PSD95 and synaptophysin in AD mice was significantly reversed. Levels of Aβ peptides and plaques were markedly reduced. Furthermore, we showed that soluble ectodomains of both type I and type III NRG1 significantly increased expression of Aβ-degrading enzyme neprilysin (NEP) in primary neuronal cultures. Consistent with this finding, immunoreactivity of NEP was increased in the hippocampus of AD mice. These results suggest that NRG1 provides beneficial effects in candidate neuropathologic substrates of AD and, therefore, is a potential target for the treatment of AD.

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Towards a Regenerative Therapy for the Lacrimal Gland and Dry Eyes

The lacrimal gland provides moisture for the eyes, and like all parts of our physiology is prone to decline and failure in old age. Dry eye conditions, some of which are painful and debilitating, are common in old people. Researchers here demonstrate a cell therapy to spur regeneration of the lacrimal gland in an animal study, a step along the road to achieving the same thing in humans:

The eye's lacrimal gland is small but mighty. This gland produces moisture needed to heal eye injuries and clear out harmful dust, bacteria and other invaders. If the lacrimal gland is injured or damaged by aging, pollution or even certain pharmaceutical drugs, a person can experience a debilitating condition called aqueous deficiency dry eye (ADDE) - sometimes called "painful blindness." If injured, a healthy lacrimal gland naturally regenerates itself in about seven days. When diseased and chronically inflamed, however, regeneration stops - and scientists are not sure why.

Researchers looked at whether they could kick start regeneration by injecting progenitor cells into the lobes that make up the lacrimal gland. Progenitor cells are similar to stem cells in their ability to differentiate into different kinds of tissue. In this study, the researchers used progenitor cells that were poised to become epithelial tissue, a key component of the lacrimal gland. The researchers knew they faced a major challenge: sorting and separating "sticky" epithelial cell progenitors without destroying them. "We had to figure out how to dissociate the tissue into single cells without completely obliterating everything." The researchers solved this problem by developing markers to label the cells of interest and then testing different enzymes and other reagents to draw them out of tissues.

With these cells in hand, the researchers injected them into the lacrimal glands of mouse models of Sjogren's syndrome, an autoimmune disease that results in ADDE, dry mouth and other symptoms. The team used only older, female mice because ADDE most commonly strikes that demographic in humans. The treated mice showed a significant increase in tear production, indicating - for the first time - that epithelial cell progenitors could repair the lacrimal gland. Further tests suggested that epithelial cell progenitors helped by restoring the connection between cells called myoepithelial contractile cells and the lacrimal gland's secretory cells, which produce tears. The next step in this research will be to study how long the improvement in the lacrimal gland lasts after progenitor cell injections.

Development of a Cell Therapy to Increase Remyelination in the Brain

In this open access paper, results are presented for an animal study of an approach to increasing the pace of remyelination in the brain. Myelin acts as sheathing for the axons that connect nerve cells; when it is degraded, insufficiently maintained, or damaged, the result is dysfunction in the nervous system. A range of demyelinating diseases result from the loss of myelin in specific locations, many of which are life-threatening. To a lesser degree, loss of myelin occurs over the course of aging for all of us. It is unclear as to the degree that this process contributes to age-related decline in cognitive and physical function, but given what is known from the observation of demyelinating diseases it is unlikely that the losses are harmless. Thus it is well worth paying attention to progress towards therapies that can increase the rate of remyelination, as it is likely that a robust and effective approach would be useful for all older individuals:

Microglia play critical but incompletely understood roles in propagation and resolution of central nervous system (CNS) injuries. These cells modulate neuroinflammation, produce factors that regulate activities of astrocytes, oligodendrocytes, and neurons, and clear debris to provide an environment for oligodendrocytes to begin to remyelinate neurons. Separately, limited information is available concerning the role of human blood monocytes in the dynamics of repair of brain injury. Circulating human monocytes include subpopulations that differ in their ability to migrate to tissues, proliferate, and form inflammatory or reparative macrophages at sites of injury. Based on experiments in rodents, several groups have proposed that cell products composed of human monocytes could be considered as candidates for the treatment of injury-induced CNS demyelination. CD14+ monocytes present in human umbilical cord blood (CB) are among these candidates.

We have recently developed DUOC-01, a cell therapy product composed of cells with characteristics of macrophages and microglia that is intended for use in the treatment of demyelinating CNS diseases. DUOC-01 is manufactured by culturing banked CB-derived mononuclear cells (MNCs). The studies described in this report were designed to provide proof of concept for the use of DUOC-01 in treatment of demyelinating diseases that do not arise from enzyme deficiency. To accomplish this, we assessed the ability of DUOC-01 to promote remyelination of mouse brain after cuprizone-induced (CPZ-induced) demyelination, a model that has been widely used to study the mechanisms and cellular dynamics of remyelination in the corpus callosum (CC) region, and also to test the effects of various interventions, including cell therapy agents.

We showed, to the best of our knowledge for the first time, that CPZ feeding in immunodeficient mice results in reversible demyelination in the CC with a time course similar to the process in immune-competent mouse strains, and that this model can be used to assess the activity of human cell therapy products in promoting brain remyelination. Using this model, we demonstrate that the DUOC-01 cell product accelerates brain remyelination following CPZ feeding. We also show that uncultured CD14+ CB cells that give rise to DUOC-01 also accelerate remyelination, but significantly less actively than DUOC-01 cells. A comparison of whole-genome expression arrays of CB CD14+ monocytes and DUOC-01 revealed large differences in gene expression, and helped identify candidate molecules that may participate in remyelination. We subsequently confirmed that cells in the DUOC-01 product express and secrete several factors that promote myelination by several mechanisms.

Enhancing Cell Therapy to Enable Greater Recovery Following Stroke

Researchers here demonstrate a method of improving the effectiveness of a stem cell therapy targeted to brain tissues, enabling the treatment to repair more of the damage caused by a stroke:

A team of researchers has developed a therapeutic technique that dramatically increases the production of nerve cells in mice with stroke-induced brain damage. The therapy relies on the combination of two methods that show promise as treatments for stroke-induced neurological injury. The first consists of surgically grafting human neural stem cells into the damaged area, where they mature into neurons and other brain cells. The second involves administering a compound called 3K3A-APC, which the scientists have shown helps neural stem cells grown in a petri dish develop into neurons. However, it was unclear what effect the molecule, derived from a human protein called activated protein-C (APC), would have in live animals.

A month after their strokes, mice that had received both the stem cells and 3K3A-APC performed significantly better on tests of motor and sensory functions compared to mice that received neither or only one of the treatments. In addition, many more of the stem cells survived and matured into neurons in the mice given 3K3A-APC. "This animal study could pave the way for a potential breakthrough in how we treat people who have experienced a stroke. If the therapy works in humans, it could markedly accelerate the recovery of these patients."

To confirm that the stem cells were responsible for the animals' improved function, the researchers used a targeted toxin to kill the neurons that had developed from them in another group of mice given the combination therapy. These mice showed the same improved performance on the tests of sensory and motor functions prior to being given the toxin but lost these gains afterwards, suggesting that the neurons that grew from the implanted cells were necessary for the improvements. In a separate experiment, the team examined the connections between the neurons that developed from the stem cells in the damaged brain region and nerve cells in a nearby region called the primary motor cortex. The mice given the stem cells and 3K3A-APC had many more neuronal connections, called synapses, linking these areas than mice given the placebo. In addition, when the team stimulated the mice's paws with a mechanical vibration, the neurons that grew from the stem cells responded much more strongly in the treated animals. "That means the transplanted cells are being functionally integrated into the host's brain after treatment with 3K3A-APC. No one in the stroke field has ever shown this, so I believe this is going to be the gold standard for future studies."

Cells can Transfer Lysosomes, Spreading Damaging Age-Related Waste Materials

It is known that cells can transfer mitochondria from one to another under some circumstances, and here researchers demonstrate that they can transfer lysosomes as well. The lysosomes in a cell play the role of recycling units, breaking down damaged structures and waste proteins. Unfortunately there are some forms of waste that our biochemistry cannot manage, and these compounds accumulate over time into a harmful mix called lipofuscin. In old tissues, long-lived cells have clogged and malfunctioning lysosomes, unable to perform the task of recycling waste. This spirals downwards into a garbage catastrophe and the cells either die or become highly dysfunctional themselves. This process of resilient waste accumulation in lysosomes is one of the root causes of aging and age-related disease.

The research here focuses on just one form of damaged protein and one class of conditions caused by the accumulation of that protein, but the transfer of lysosomes noted by the researchers has broad implications for the more general process of lysosomal dsyfunction in aging. If cells are transferring lysosomes in all tissues then this will act to dilute damage for the worst affected cells at the cost of spreading the damage more widely within important cell populations - it will be an important determinant of the way in which damage and decline progresses. That said, this is of interest but not importance given a class of therapy that can break down the waste that makes up lipofuscin. With such a tool, capable of delivering suitable enzymes to the lysosome, it doesn't matter how the waste material spreads. The SENS Research Foundation has been working on this for a while now, mining the bacterial world for suitable enzymes. Some of these have been licensed to Human Rejuvenation Technologies, and others to Ichor Therapeutics for further development for specific therapies.

Synucleinopathies, a group of neurodegenerative diseases including Parkinson's disease, are characterized by the pathological deposition of aggregates of the misfolded α-synuclein protein into inclusions throughout the central and peripheral nervous system. Intercellular propagation (from one neuron to the next) of α-synuclein aggregates contributes to the progression of the neuropathology, but little was known about the mechanism by which spread occurs. In this study researchers used fluorescence microscopy to demonstrate that pathogenic α-synuclein fibrils travel between neurons in culture, inside lysosomal vesicles through tunneling nanotubes (TNTs), a new mechanism of intercellular communication.

After being transferred via TNTs, α-synuclein fibrils are able to recruit and induce aggregation of the soluble α-synuclein protein in the cytosol of cells receiving the fibrils, thus explaining the propagation of the disease. The scientists propose that cells overloaded with α-synuclein aggregates in lysosomes dispose of this material by hijacking TNT-mediated intercellular trafficking. However, this results in the disease being spread to naive neurons. This study demonstrates that TNTs play a significant part in the intercellular transfer of α-synuclein fibrils and reveals the specific role of lysosomes in this process. This represents a major breakthrough in understanding the mechanisms underlying the progression of synucleinopathies. These compelling findings, together with previous reports from the same team, point to the general role of TNTs in the propagation of prion-like proteins in neurodegenerative diseases and identify TNTs as a new therapeutic target to combat the progression of these incurable diseases.

Shorter Period of Rapamycin Treatment in Mice Produces Greater Slowing of Aging

Rapamycin, an immunosuppressant and MTOR inhibitor, is known to slow aging in mice - though it has been debated whether this extension of life span is actually a slowing of aging versus a lower rate of cancer. Researchers here try a variety of different treatment regimens and find that a comparatively short period of rapamycin treatment in mouse middle age produces better effects than the longer term dosage that has been standard in studies. The publicity materials emphasize the high points and the outliers in the mouse data; I'd recommend reading the paper for a more responsible and overall view of the outcomes.

Even with improved results and possibly a new longevity record for this mouse species, I don't think the improved outcomes much alter the overall picture for trying to slow the processes of aging in this way, by altering metabolism towards the sort of changes known to occur in response to calorie restriction. It is, however, interesting to consider what must be going on in mouse biochemistry to allow a shorter intervention to have a larger effect than a longer intervention. One possibility is that the longer intervention does in fact have all of the beneficial effects, but that the unpleasant side-effects of rapamycin begin to outweigh those benefits greatly as the mice get older. Regardless, keep in mind that mice have very plastic life spans - interventions such as calorie restriction and growth hormone receptor knockout that extend life in mice by 40-70% are known not to have large effects on longevity in humans, and we should expect that to be the case for the beneficial side of rapamycin as well.

Rapamycin, approved by the FDA for certain organ transplant recipients, is already known to extend life in mice and delay some age-related problems in rodents and humans. Still, many questions prevail about when, how much and how long to administer rapamycin, what its mechanisms of action are in promoting healthy aging, and ways to avoid serious side effects. Researchers showed that a transient dose of rapamycin in middle age was enough to increase life expectancy and improve measures of healthy aging. The scientists treated mice with rapamycin for 90 days starting at 20 months of age, approximately the mouse equivalent of a 60 year old person. The control and rapamycin-treated mice were maintained identically both before and after the treatment period. Remarkably, the rapamycin treated mice lived up to 60 percent longer after the treatment was stopped, compared to the animals that received a mock control treatment.

This, the researchers said, seems to be the biggest increase in life expectancy ever reported in normal mice from a medication. "It's quite striking that short-term rapamycin treatment had such a lasting impact on health and survival after the treatment was stopped." The reasons behind this outcome aren't completely clear, according to the researchers, but one interpretation might be that the animals were, to some degree, rejuvenated by the treatment and became biologically younger than their actual age. The most-senior mouse in the study was Ike, the namesake of a relative of one of the researchers. The mouse Ike lived 1400 days. For a person, that would be like hailing a 140th year birthday. "To our amazement, considering the relatively small size of the group of mice we studied, Ike might have been one of the longest lived mice of his kind." Ike was a wild-type C57BL/6, a designation for the one of the most common sub-strains of mice.

On the other hand, some of the side effects observed during the study were less than celebratory. The cautionary findings, the researchers noted, illustrate the need to better understanding the relationship between the dose of rapamycin and its beneficial as well as detrimental effects. The researchers saw a gender difference when higher doses of rapamycin were given: males outlived the females. At lower doses, both male and female mice had longer lives, compared to untreated mice. Higher doses can make female mice more susceptible to aggressive cancers of blood-forming cells and tissue. At the same time, middle-aged female mice receiving high-doses of rapamycin were less likely to develop other types of cancer. The transient rapamycin treatment also changed the composition of the microbiome - the collection of bacteria and other microbes - in the guts of the mice. They had more segmented, filamentous bacteria of a type not usually present in high numbers in aged mice. While these bacteria are not invasive, they adhere tightly to the cells of the intestinal wall and may encourage the formation of immune cells in the mouse. Otherwise, the influence of this gut microbiome change from rapamycin on the health of an animal, for good or bad, and whether the same thing happens in humans, has not been determined.

Ghrelin Receptor and Inflammaging

Ghrelin is related to the hunger response, but has a very broad range of influences on many tissues and systems, including immune system activities. Inflammaging is the name given to the inflammation-focused view of the characteristic decline and dysfunction of the immune system with aging. While increased levels of inflammation occur for everyone due to immune system aging, those people who allow themselves to become overweight suffer a greater level of chronic inflammation, driven by the way in which metabolically active visceral fat tissue provokes immune activation. The research here joins all of these dots, and the scientists involved demonstrate that removing the ghrelin receptor in mice can suppress the influence of fat tissue on chronic inflammation:

"To date, ghrelin is the only known appetite-stimulating hormone. The pharmaceutical industry has been calling ghrelin 'the key to obesity' since its discovery. We investigated the impact of ghrelin signaling on adipose tissue macrophages, in order to understand the role of ghrelin signaling in obesity." Hunger stimulates ghrelin in the gut, which activates brain regions where the ghrelin receptor, growth hormone secretagogue receptor, or GHS-R, is highly expressed, triggering the hunger sensation. Ghrelin enhances appetite and increases weight gain, promoting obesity and consequent insulin resistance.

Obesity, in essence, is a condition characterized by low-grade chronic inflammation in adipose tissues. Adipose tissue serves as a major endocrine organ, secreting various hormones and cytokines which play crucial roles in normal metabolism and obesity-associated dysfunctions. Adipose tissue macrophages, or ATMs, are a major mediator of inflammation in adipose tissues, which are closely linked to insulin resistance. Macrophages are a type of white blood cells that surround and digest microbes, pathogens and other foreign substances. "Macrophages are a major mediator of inflammation in the body. Increased macrophage infiltration in adipose tissues has been shown to positively correlate with age-associated metabolic complications, neurodegenerative diseases and cardiovascular diseases."

ATMs consist of two subsets - pro-inflammatory M1 and anti-inflammatory M2. M1-like macrophages are associated with an obese and insulin-resistant state, while M2-like macrophages are associated with a lean and insulin-sensitive state. M1-like macrophages release pro-inflammatory cytokines to inhibit insulin action in the tissues. On the other hand, M2-like macrophages release anti-inflammatory cytokines. "We have found that the GHS-R functions as a key regulator of age-associated adipose tissue inflammation. The removal of GHS-R shifts macrophages toward an anti-inflammatory state." Aging is commonly accompanied by increased fat mass and chronic low-grade inflammation, so concurrences of obesity and insulin resistance become significantly greater as people get older.

GHS-R global null mice - with the GHS-R removed in all cell types - showed a macrophage profile shifted toward the anti-inflammatory M2, exhibiting a healthier lean and insulin-sensitive phenotype. "Old mice with GHS-R deletion showed a reduction in macrophage infiltration, M1/M2 ratio and pro-inflammatory cytokine production in adipose tissues." The new findings suggest suppressing the ghrelin receptor may serve as a new therapeutic strategy for inflammation and obesity in aging. The study indicates the ghrelin receptor plays an important role in macrophages, which can have profound implications on obesity and insulin resistance. Current research using global null mice cannot determine whether the phenotype is resulted in by the effect of GHS-R in macrophages alone, however. Scientists must determine the macrophage-specific effects of GHS-R, and understand precisely how ghrelin signaling works, in order to avoid unintended side effects. The researchers are now developing new mouse models which would enable them to delete GHS-R selectively in macrophages.

Marmosets in Aging Research

The use of animals in the study of aging has always meant striking a balance between species life span and distance from humans in the evolutionary tree of life. Very short-lived species such as worms and flies allow for much cheaper, faster studies, but the biochemistry of these species is more distant from ours, meaning fewer of the results are relevant to human medicine. Fortunately many of the fundamental processes of aging are near universal in animal life, all the way down to yeast colonies, so it is possible to perform useful exploratory research at a reasonable price. Still, researchers are ever in search of a better class of animal, one that has a much greater similarity to humans without the very lengthy life span. Even using short-lived mammals such as mice, that live for a few years, results in studies that are expensive and long-running when considered as a fraction of the length of a career, or placed against the size of most grants. Further, even mice have sometimes meaningful differences when compared with humans, such as their telomere dynamics. If large amounts of time and money are to be spent, then researchers would ideally want to run studies of aging in primates, and this has happened for decades-long studies of calorie restriction in rhesus macaques. Such studies are highly unlikely to happen again in the foreseeable future, however, given a broad dissatisfaction with the planning and outcomes of these examples. Researchers have started to look at the small selection of comparatively short-lived primates instead, and currently there is a faction advocating the use of marmosets:

Great leaps forward in our understanding of the basic biology of aging, including interventions that extend longevity, have come about from using common laboratory animal models. As we now strive to apply these findings for human benefit, a serious concern arises in how much of this research will directly translate to normal, largely healthy, and genetically varied populations of people. Laboratory animals, including rodents, are only distantly related to humans and have undergone different evolutionary pressures that likely have driven species-specific idiosyncrasies of aging. Due to our long lifespans, any outcomes of longevity interventions in human studies are unlikely to be discovered even during the research careers of current graduate students. There is then strong rationale for testing whether the interventions discovered that slow aging in laboratory rodents, such as dietary restriction, mTOR (mechanistic target of rapamycin) inhibition, or acarbose, will also extend the lifespan of species more closely related to humans. In this context, the calorie restriction studies utilizing non-human primates are prime examples of this approach. However, the rhesus macaques used in these studies also have relatively long lifespans which required time commitment in the order of decades to accomplish the recently published final results.

Most non-human primates that can be kept in healthy laboratory populations have relatively long lifespans, but the small South American common marmoset (Callithrix jacchus) may offer a number of advantages over other non-human primate species, particularly for researchers interested in aging. The normal lifespan of the common marmoset is the shortest of any anthropoid primate, with an average lifespan in captivity of approximately 7-8 years and maximum lifespans reported between 16 and 21 years. While much longer-lived than rodents, the average age of marmosets is more manageable for a designed longevity study than the 25-year average lifespan of rhesus macaques or the 70-plus average lifespan of humans. In addition, marmosets in a closed colony have a natural adult mortality that drives a decline in their cumulative survival rate from about 85 to 35% that occurs between 5 and 10 years of age. In other words, a carefully designed intervention study could occur over the time course of a single NIH RO1 granting period using this non-human primate.

Similar to other non-human primates, the sequenced marmoset genome has high homology (more than 93%) with that of humans. Many of the common molecular biology tools, including antibodies, have relatively good cross-species recognition. Marmosets have a growing track record as a non-human primate model used for a number of diseases and pathologies that are generally considered as age-related, including Parkinson's disease, respiratory diseases, and infectious diseases. Moreover, marmosets display age-related changes in pathologies associated with diabetes, cardiac disease, cancer, and renal disease similar to those seen in humans. Marmosets thus represent a complement to the existing non-human primate models used to study aging and, in particular, a model in which effects on longevity might be assessed in a relatively timely manner. Despite this promising outlook, there are some potential challenges to using the common marmoset as a non-human primate model to study aging. Like other non-human primates, there is much less genetic tractability in this species relative to the mouse, which must be taken into account when designing studies on the biology of aging. However, transgenic marmosets have been previously generated and new technologies including CRISPR/Cas systems may lead the way in developing new, genetically modified marmoset models for the study of age-related diseases or the basic biology of aging.

A Scanning Approach to Detect Transthyretin Amyloid Buildup in the Heart

Accumulation of transthyretin amyloid is one of the root causes of aging. This is a form of protein misfolding that products harmful deposits, amyloids, in tissues. In recent years this type of amyloid has been identified as the major cause of death in supercentenarians, but it was not until very recently understood to also be a significant cause of heart failure in the earlier stages of old age. Researchers here demonstrate a scanning methodology to detect transthyretin amyloid in heart tissue, which should hopefully lead to more resources directed towards finalizing the development of an existing therapeutic approach to breaking down and clearing this amyloid. That approach has been trialed successfully in a few patients, but is currently languishing in the endless regulatory pipeline somewhere prior to clinical availability. It is madness that so little funding and urgency is given to this sort of development, especially given the existence of an approach that appears to work: transthryretin amyloid clearance should be undertaken every few years by pretty much every adult over the age of 40, and the outcome would be significantly less heart disease.

A type of heart failure caused by a build-up of amyloid can be accurately diagnosed and prognosticated with an imaging technique, eliminating the need for a biopsy. The technique may also detect the condition - called transthyretin-related cardiac amyloidosis (ATTR-CA) - before it progresses to advanced heart failure. "This is a huge advance for patients with ATTR-CA, which is under recognized and often misdiagnosed. This test will spare certain patients from having to undergo a biopsy in order to get a definitive diagnosis. Many people with ATTR-CA are frail and elderly, so being able to avoid a biopsy, even when it can be done with a less-invasive catheter-based procedure, is a significant step forward."

ATTR-CA is one of many types of amyloidosis, a condition in which a protein breaks down and forms fibrils that deposit in organs and tissues, eventually causing the organs to fail. In ATTR-CA, the transthyretin protein breaks down and forms amyloid fibrils, which mainly accumulate in the heart, disrupting its function. Different types of amyloidosis require different treatments, so obtaining an accurate diagnosis is critical. ATTR-CA was once thought to be rare, but it's now known that ATTR-CA resulting from a normal variant of the transthyretin protein has a prevalence of about 32 percent in patients with heart failure over age 75 years at autopsy. The prevalence in hospitalized patients with heart failure is about 13 percent.

The diagnostic tool evaluated in the study is derived from bone scintigraphy, a form of single-photon emission computed tomography, or SPECT, that is conventionally used to detect bone cancer. In bone scintigraphy, patients are injected with a radioactive isotope with a particular affinity for bone that has remodeled due to bone cancer. Early on, researchers noticed that the isotope, technetium 99m pyrophosphate (Tc 99m PYP), also gravitates to amyloid deposits in the heart, a defining characteristic of ATTR-CA. In this study, the researchers examined the diagnostic accuracy of the Tc 99m PYP test for ATTR-CA in a retrospective study of 179 amyloidosis patients (121 with ATTR and 50 with other types). The researchers found that the imaging test was able to correctly identify ATTR in 91 percent of those diagnosed with the disease, and was able to rule out ATTR-CA in 92 percent of those with other forms of amyloidosis or no amyloidosis.

A Potential Way to Speed the Recovery Phase of an Immune System Reboot

There is great potential in the destruction and recreation of the immune system: the removal of all immune cells and replacement with new cells. This is an approach capable of curing autoimmune conditions, but perhaps more importantly it might also be used to clear out much of the dysfunction of the aged immune system. Immune system decline is an important component of the frailty of aging, and it speeds other aspects of the aging process through inflammation and a growing failure to monitor and destroy potentially harmful cells, such as those that become senescent. Just recently researchers made real progress on the immune system destruction front, finding a way to achieve that goal without harmful chemotherapy, and to match that advance, here is news of a potential method to improve the restoration phase of the process:

New research has shown how a cell surface molecule, Lymphotoxin β receptor, controls entry of T-cells into the thymus; and as such presents an opportunity to understanding why cancer patients who undergo bone-marrow transplant are slow to recover their immune system. The thymus, which sits in front of the heart and behind the sternum, imports T-cell precursors from the bone marrow and supports their development into mature T-cells that fight off dangerous diseases. T-cells are often the last cells to recover in cancer patients receiving bone marrow transplants. Though the cancer is cured, patients are often left with an impaired immune system that can take years to recover. Researchers found that Lymphotoxin β receptor was required to allow the entry of T-cell progenitors to the thymus both in a healthy state, and during immune recovery following bone-marrow transplantation.

Significantly, the team also found that antibody-mediated stimulation of Lymphotoxin β receptor in mouse models enhanced initial thymus recovery and boosted the number of transplant derived T-cells. "Post-transplantation, T-cell progenitors derived from the bone marrow transplant can struggle to enter the thymus, as if the doorway to the thymus is closed. Identifying molecular regulators that can 'prop open' the door and allow these cells to enter and mature, could well be a means to help reboot the immune system. This is just one piece of the puzzle. It may be that there are adverse effects to opening the door to the thymus, but identifying a pathway that regulates this process is a significant step." Following these positive findings the team aim to move towards in-vitro samples of human thymus to examine the role that Lymphotoxin b receptor might play in regulation of thymus function in humans.

A Bleak Outlook on Aging

As illustrated by this study, most people don't think about their own future aging, and when they do they are unaware that we stand on the verge of new medical technologies that will greatly extend healthy life spans. We humans have evolved a masterful ability to avoid thinking about the future when it looks likely to be unpleasant. That is a useful trait when the unpleasant future is inevitable and unavoidable, as was the case for aging and age-related disease for the entirety of human history. Now, however, when it has become possible and plausible to produce effective rejuvenation therapies in the decades ahead, this ability to put the future out of sight and out of mind works against us. It is hard to get people to commit to planning and support of rejuvenation research in the matter of adjusting the course of their own future aging, even when the adjustment is entirely beneficial: everything they have been taught when young, formally and informally, has led them to put away considerations of later life as an ugly thing that they don't want to think about. Yet in reality, and as a further confounding outcome, people are happier when older, up to the point at which the decline into ill health becomes very evident and a real struggle. That effect is probably a measure of just how much value we place on financial security and a higher position in the hierarchy of society; from the perspective of contentment, these aspects of later life can outweigh the decline of health and function for a large fraction of a life span. This, again, may well be another reason why it is hard to obtain support to bring an end to aging.

Why do some people want to live a very long time, while others would prefer to die relatively young? A team of researchers investigated how long young and middle-aged adults in the United States say they want to live in relation to a number of personal characteristics. The results showed that more than one out of six people would prefer to die younger than age 80, before reaching average life expectancy. There was no indication that the relationship between preferring a life shorter or longer than average life expectancy depended on age, gender or education. The study is one of the first to investigate how younger adults perceive and anticipate their own aging. Using data from a telephone survey of over 1600 adults aged 18 to 64 years, the authors also found that one-third would prefer a life expectancy in the eighties, or about equal to average life expectancy, and approximately one-quarter would prefer to live into their nineties, somewhat longer than average life expectancy. The remaining participants said they hope to live to 100 or more years. Participants were on average 42 years old, half were women and 33 per cent were university graduates.

"We were particularly interested in whether how long people want to live would be related to their expectations about what their life in old age will be like." The results, which were controlled for overall happiness, confirmed that having fewer positive old age expectations was associated with the preference to die before reaching average life expectancy. On the contrary, having fewer negative old expectations was associated with the preference to live either somewhat longer or much longer than average life expectancy. "Having rather bleak expectations of what life will be like in old age seems to undermine the desire to live up to and beyond current levels of average life expectancy. People who embrace the 'better to die young' attitude may underestimate their ability to cope with negative age-related life experiences as well as to find new sources of well-being in old age."


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