Fight Aging! Newsletter, February 2nd 2015

February 2nd 2015

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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  • How to Best Hinder or Halt the Aging Process, A Roundtable Discussion on Regenerative Medicine
  • Yet Another Application of Stem Cell Based Regenerative Medicine to Hair Restoration
  • The Slow and Ineffectual Path to Aging Interventions for Humans
  • Comparing Senescent Cells and Cells From Progeria Patients
  • A Good High Level Vision for Treating Aging Attached to an Unambitious Near Term Plan for Results
  • Latest Headlines from Fight Aging!
    • Better Proteostasis in Long-Lived Species
    • Intermittent Fasting and Hippocampal Biochemistry
    • On the Decline of Chaperone-Mediated Autophagy in the Liver
    • An Early Negative Result for Tau Immunotherapy
    • More on the Klotho Allele Associated with Better Cognition
    • A Historical Analysis of Lifespan for the Privileged
    • Considering Amyloid Beta and Alzheimer's Disease
    • Executive Dysfunction Predicts Stroke Risk
    • What to Do About Modified Low-Density Lipoproteins?
    • More Work on DNA Methylation Patterns and Aging


One slice of the comprehensive package of biotechnologies needed to reverse the causes and consequences of degenerative aging involves next generation cell therapies. The aged body has lost needed cells, while other vital but small cell populations fall into a state of damage and dysfunction. Replacements will have to be generated, and cell therapies are how this goal will be achieved. These future therapies are presently in the early stages of development; they follow on from and will greatly improve on today's stem cell transplants. The introduction of new stem cells is the present best tool for achieving beneficial changes in native cell behavior, but the destination for this field is to discard the stem cells and simply make the desired changes directly. The stem cell therapies available now are a stepping stone to future treatments that directly repair cells and adjust their behavior in situ.

Cell therapies are neither more noteworthy nor more needed than any of the other items in the proposed rejuvenation toolkit, such as repair of mitochondrial damage and targeted clearance of metabolic waste, but they are considerably further along in the long path leading from first concepts to commercial therapies. A lot of money is available for stem cell research, and there is much to be said for making hay while the sun shines. Success here in steering groups within the community towards the treatment of aging will hopefully lead to successful businesses that branch out into other needed areas of development in rejuvenation biotechnology.

The 2014 World Stem Cell Summit was held last month in Texas. As you might expect, there is an ongoing discussion at such events prompted by those who are interested in going beyond merely treating age-related disease in its late stages, the traditional approach in medicine that has produced only marginal gains when it comes to extension of healthy life. These researchers want to turn the tools of regenerative medicine to tackle the causes of aging:

How to Best Hinder or Halt the Aging Process, a Roundtable Discussion on Regenerative Medicine

Medicine is the diagnosis, treatment, and, increasingly, hopefully, the prevention of what ails us. Most people's experience of medicine is likely focused on diagnosis and, unfortunately, the treatment of symptoms, the mitigation of the condition, with time bringing an amelioration of the problem. The excitement of regenerative medicine is the ability to replace or regenerate cells, tissues, or organs. So instead of a lifetime of taking injections, tablets, or using prostheses, patients actually become healthy again. Looking at tissue engineering, the classic approach is cells + scaffold = restored functionality.

It may be useful for researchers to think further out of the box regarding regenerative medicine than the areas that the term conventionally encompasses. Stem cell therapies are, in essence, a form of damage repair: they restore the number of cells of a given type that have been depleted, thus leading to ill-health. But tissue engineering restores not only cell number but also the structure of the extracellular matrix, among other things. Emerging technologies, often utilizing gene therapy or immune stimulation, powerfully complement these approaches. For example, in many cases they act to remove superfluous cells or detritus that the body is unable to eliminate naturally. The potential combined benefit of these therapies and classic regenerative medicine far exceeds the sum of its parts so there is considerable value in viewing the entire arsenal as facets of the same kind of medicine and thereby promoting cross-disciplinary thinking and research.

Clearly, heterochronic parabiotic studies have shown that the aged environment is hindering normal regenerative processes. How much these results can be recapitulated in humans is up for grabs right now. Anyone who works with rodents and humans knows that rodents are much more forgiving in terms of recovery from injury than humans. If the disease is one of aging, like age-related heart disease, macular degeneration, Alzheimer disease, or Parkinson's disease, we have no choice but to develop therapies that will work for older people. What is regenerative medicine if not the treatment of an event or condition that is increasingly likely to occur with years lived?


It would be an interesting and possibly rather depressing exercise to compare funding for reversal of age-related hair loss to that for the effective treatment of various other aspects of aging. Hair restoration, I think, is fairly well funded in comparison with many lines of research that I consider to be far more important. What moves the needle for you: looking good or living in good health? It would be a tremendous improvement over the present state of the human condition to find oneself at age 80 and balded, yet with internal organs repaired by rejuvenation biotechnologies, and the health and vigor to complain loudly about the terrible state of hair regrowth medicine. Instead I rather fear the order of development is going to be the other way around, with elderly people continuing to crumble inside in a score of ways yet having the option of a naturally flowing head of hair should they so desire. Progress happens most rapidly where the funding flows, and vanity has never been well restrained by common sense.

In reality we'd like to see unrestrained research funding sufficient for rapid progress on all fronts of regeneration and rejuvenation, whether merely vain and secondary or connected to the essential function of organs actually required for healthy life. Funding for medical research is such a tiny fraction of the resources spent on frivolous things that there is always room for growth through persuasion.

Researchers develop method to induce human hair growth using pluripotent stem cells

"We have developed a method using human pluripotent stem cells to create new cells capable of initiating human hair growth. The method is a marked improvement over current methods that rely on transplanting existing hair follicles from one part of the head to another. Our stem cell method provides an unlimited source of cells from the patient for transplantation and isn't limited by the availability of existing hair follicles."

The research team developed a protocol that coaxed human pluripotent stem cells to become dermal papilla cells. They are a unique population of cells that regulate hair-follicle formation and growth cycle. Human dermal papilla cells on their own are not suitable for hair transplants because they cannot be obtained in necessary amounts and rapidly lose their ability to induce hair-follicle formation in culture. "We developed a protocol to drive human pluripotent stem cells to differentiate into dermal papilla cells and confirmed their ability to induce hair growth when transplanted into mice. Our next step is to transplant human dermal papilla cells derived from human pluripotent stem cells back into human subjects. We are currently seeking partnerships to implement this final step."

Derivation of Hair-Inducing Cell from Human Pluripotent Stem Cells

Dermal Papillae (DP) is a unique population of mesenchymal cells that was shown to regulate hair follicle formation and growth cycle. During development most DP cells are derived from mesoderm, however, functionally equivalent DP cells of cephalic hairs originate from Neural Crest (NC). Here we directed human embryonic stem cells (hESCs) to generate first NC cells and then hair-inducing DP-like cells in culture.

We showed that hESC-derived DP-like cells (hESC-DPs) are able to induce hair follicle formation when transplanted under the skin of immunodeficient NUDE mice. Engineered to express GFP, hESC-derived DP-like cells incorporate into DP of newly formed hair follicles and express appropriate markers. We demonstrated that BMP signaling is critical for hESC-DP derivation since BMP inhibitor dorsomorphin completely eliminated hair-inducing activity from hESC-DP cultures.

DP cells were proposed as the cell-based treatment for hair loss diseases. Unfortunately human DP cells are not suitable for this purpose because they cannot be obtained in necessary amounts and rapidly loose their ability to induce hair follicle formation when cultured. In this context derivation of functional hESC-DP cells capable of inducing a robust hair growth for the first time shown here can become an important finding for the biomedical science.


A point I frequently make is that while there exists a wide range of potential approaches to the development of therapies to treat aging, it is important to divide these approaches into two buckets. Firstly there are potential therapies that aim to repair the root cause cellular and molecular damage that leads to degenerative aging, and which are in principle capable of rejuvenation, indefinite prevention of all age-related disease, and indefinite extension of healthy life. Whether any particular package of implemented therapies achieves this or not is a matter of how much damage is repaired: it depends on the effectiveness and coverage of the treatments in question. Are they repairing all the types of damage that cause aging, and are they repairing enough of each type in all tissues that matter?

The larger second category contains all other potential therapies that do not aim to repair the fundamental damage that causes aging. These either aim to alter the operation of metabolism to slow down the accumulation of that damage, or try to adjust or repair secondary effects of the root cause damage - neither of which is going to be anywhere near as effective an approach, even though they may be far more troublesome and costly to implement. These therapies are not in principle capable of more than fleeting and partial rejuvenation, and definitely can't achieve indefinite prevention of disease or extension of healthy life.

Outside the stem cell research community there is far more ongoing work on the second type of treatment at this time. This might make little sense to an outsider who imagines that things proceed completely rationally in the scientific world. Developing drugs to tinker with metabolism based on the study of dysfunctional end states of disease is the modus operandi of much of modern medicine, and has been for a century. There is a lot of inertia in the institutions involved, and mere details such as this being a far worse approach to take in work on treating aging won't slow down this train all that much. Change must come from disruption of the entire status quo, and disruption must come from the newcomers and the iconoclasts and the rebels. It is happening, thanks to the work of organizations like the Methuselah Foundation and SENS Research Foundation, but in the highly regulated medical research and development community this sort of change is slow. It has taken a decade of persistent advocacy for even some of the most evident and easily explained of the SENS proposals, such as senescent cell clearance, to get a little traction in the last couple of years.

(Remember that the SENS proposals for the treatment of aging really aren't the SENS proposals at all: they are a consensus on aging and our biology derived from scores of research groups and publications from past years, drawn together and presented in a coherent fashion. The SENS proponents are organizers. Every field of science goes through periods of great diversity and expansion that must necessarily be followed by a process of synthesis, as the shards of the field have diverged too far for the researchers involved to have a good vision of the whole. The SENS view of aging is a part of an ongoing period of synthesis of all fields of medical research relevant to aging: a great deal was discovered over the past thirty years, but only in the past decade has an earnest reconciliation and exchange of knowledge begun for the purposes of building new technologies).

Meanwhile, even as researchers could be making significant progress on actual rejuvenation therapies were there the funding and the will, the mainstream continues to consider itself radical for initiating tests of existing drugs that might, maybe, cause some health benefits in humans, and possibly an extension of life by just a few years if taken over the long term. It is a terrible thing to watch, knowing that time is ticking away for all of us.

Aging interventions get human (PDF)

Over the last three decades, aging research has made great strides. At least in non-vertebrate animal models such as yeast and worms, it is possible to extend lifespan through reduced or ablated expression of hundreds of genes. The number of genes tested in mice are substantially less but the data so far is consistent with modulation of aging by numerous genes and pathways. More importantly, evidence exists that many of these genetic interventions extend healthspan and protect against the onset of age-associated chronic diseases. Recently, small molecules have entered center stage, with both natural products and clinically approved compounds reported to delay aging.

These findings raise the question of whether it is possible to forestall aging as an approach to maintain vitality and delay the onset of multiple chronic diseases simultaneously. However, there are significant hurdles to testing human aging drugs and many have been skeptical that aging interventions will ever enter the clinic. Among the foremost challenges, aging is not formally considered a disease by the FDA and the prospects of testing whether drugs extend human lifespan directly promises to be a long and exorbitantly expensive process. There is also the challenge of performing clinical trials in aging individuals who are still generally healthy. Foremost among these is the extra level of safety that will need to be incorporated since care must be taken not to do harm to healthy, older people. One potential solution is to test compounds against deleterious phenotypes associated with human aging - but which compound and which phenotype? This question has been debated extensively.

Sometimes the best approach is to start testing and let the results dictate the path forward. In this vein, Mannick et al. recently reported the results of the first human aging trial. They chose a first generation derivative of the drug rapamycin (known as everolimus or RAD001), which has been shown to extend lifespan in all four major animal models of aging: yeast, worms, flies and mice. Importantly, rapamycin, which is a direct inhibitor of the mTOR kinase, can extend lifespan by 25% in mice and even show efficacy when initiated in 20 month old mice. Most studies indicate that rapamycin extends healthspan as well. Rapalogs, or rapamycin derivatives, are approved for treatment of several disease indications, but also have a range of side effects.

Mannick et al. chose to administer RAD001 to healthy people 65 and older over a six week period, followed by flu vaccine inoculation two weeks after suspending drug treatment. The findings from the Mannick study are encouraging. Importantly, Mannick et al. found efficacy at both lower dose regimens of RAD001, demonstrating at least a 1.2 fold increase in the serologic hemagglutinin inhibition geometric mean titer ratio (HI GMT) of two of the three influenza viruses represented in the vaccine at four weeks after inoculation. This is a relevant target since prior studies have shown that a 20% increase in GMT ratio has been associated with reduced influenza illness. Interestingly, RAD001 also appeared to broaden the serologic response, causing enhanced seroconversion to heterologous influenza strains not in the chosen influenza vaccine. This finding is also suggestive of enhanced protection against influenza illness.

The study by Mannick et al. is groundbreaking but it sets the stage for testing drugs associated with delayed aging in healthy older human populations. Whether rapalogs are the right drugs and immunosenescence is the right marker for healthspan remains to be determined, but it is critical for aging research to enter the clinic and this study is a fascinating initial foray.


The path of the life sciences is to learn all there is to know about human biochemistry, regardless of use or application. The path of medicine, like the path of engineering, is to take what is known today and build the best and most useful technologies possible in that environment of incomplete knowledge. In the case of senescent cells there is certainly a lot left to learn, as is the case for all cellular biology: the massed data that the research community possesses at present is only an outline in comparison to the vast forest of low-level details and interactions yet to be uncovered.

Senescent cells are those that permanently exit the cell cycle and cease replication in response to damage or circumstances such as the presence of toxins that indicates a strong possibility of damage. This serves at least initially as a defense against cancer: some portion of those cells most likely to become cancerous are removed from the picture via senescence. Unfortunately senescent cells can linger, and they behave in ways that cause harm to surrounding tissue structures. The more senescent cells there are then the worse the resulting damage. Many of these cells are destroyed by the immune system or by their own programmed cell death mechanisms, but nonetheless a sizable fraction of many tissues consist of senescent cells by the time late life rolls around. This is a material contribution to many of the dysfunctions and frailties of degenerative aging.

For all that I can repeat the summary above, scientific institutions still have a long way to go in deciphering every last aspect of cellular senescence. But in the medical world there is a very clear path to producing meaningful treatments in the very near future, which is to simply destroy these cells on an ongoing basis. This has been demonstrated in mice engineered to suffer accelerated aging, and better studies on more normal mice are presently underway. A few research groups are working on a variety of ways to clear senescent cells from tissues, but are still quite early in the process of moving from laboratory to clinical applications of research. Nonetheless, this is a very viable way to circumvent present lack of knowledge: if researchers can selectively destroy senescent cells and show benefits as a result, then for this purpose the fine details of how senescence progresses and causes harm don't really matter.

Back to the science, here is an example of ongoing investigation of some of those fine details. Here researchers compare ordinary cellular senescence with the dysfunctional state of cells obtained from Hutchinson-Gilford progeria syndrome patients. This condition has many of the appearances of accelerated aging, though it is not that, and there is some interest in understanding whether any of the mechanisms involved in progeria have relevance to normal aging:

Understanding cellular ageing

Researchers have mapped the physical structure of the nuclear landscape in unprecedented detail to understand changes in genomic interactions occurring in cell senescence and ageing. Their findings have allowed them to reconcile the contradictory observations of two current models of ageing: cellular senescence of connective tissue cells called fibroblasts and cellular models of an accelerated ageing syndrome.

In the first model, cellular senescence triggers large-scale spatial rearrangements of chromatin and the formation of dense nuclear domains called SAHF (senescence associated heterochromatic foci). Chromatin is the complex of DNA and proteins that forms the chromosomes in the nucleus. The second model uses fibroblast cells from people with a syndrome causing accelerated ageing (Hutchinson-Gilford progeria syndrome, HGPS) and these cells show reduced compaction of chromatin and do not show the creation of SAHF domains.

Unexpectedly, the researchers found that SAHF regions, thought to be highly condensed and structured, show a dramatic loss of local interconnectivity and internal structure in senescence chromatin and that this effect was also seen in the genomes from HGPS cells. "The seemingly opposite changes in chromatin behaviour between cell senescence and cells from HGPS patients have been an obstacle to understanding their contribution to ageing. Using physical interaction mapping, a direct measure of the genome architecture, our study suggests that the chromatin does initially change in a similar way in cell senescence and HGPS. We can now focus our studies on these early events common to both model systems."

Global Reorganization of the Nuclear Landscape in Senescent Cells

Cellular senescence has been implicated in tumor suppression, development, and aging and is accompanied by large-scale chromatin rearrangements, forming senescence-associated heterochromatic foci (SAHF). However, how the chromatin is reorganized during SAHF formation is poorly understood. Furthermore, heterochromatin formation in senescence appears to contrast with loss of heterochromatin in Hutchinson-Gilford progeria.

We mapped architectural changes in genome organization in cellular senescence using Hi-C. Unexpectedly, we find a dramatic sequence- and lamin-dependent loss of local interactions in heterochromatin. This change in local connectivity resolves the paradox of opposing chromatin changes in senescence and progeria. Comparison of embryonic stem cells (ESCs), somatic cells, and senescent cells shows a unidirectional loss in local chromatin connectivity, suggesting that senescence is an endpoint of the continuous nuclear remodelling process during differentiation.

That last point ties in nicely with the concept of cellular senescence as a tool initially evolved to steer embryonic development, and only later emerging as a system to reduce cancer incidence in damaged tissues.


Not so long ago, the standard rhetoric on treating aging from the research establishment was silence. Talking in public about research indicating that aging could in principle be treated to extend healthy life was strongly discouraged, and was in fact a great way to harm your ability to raise funding and build a career in the field. That state of affairs continued for far too long, and held back progress as a result. Over the past fifteen years advocates within and outside the research community have brought about real change, however, and now many researchers talk about the prospects for slowing or reversing degenerative aging with no fear of repercussion. Indeed, anyone with a sense for these things should be able to see that the application of aging and longevity research is about to blossom into a massive, productive, and very energetic field of medicine: names will be made, and great deeds done.

At this stage in the process, things have advanced to the point at which we see bold statements of principle from researchers previously silent, but which are coupled to unambitious plans of action for the next few decades that are almost certainly doomed to produce marginal outcomes at best. The inertia of the research and development methodology that dominated the past fifty years guides researchers into drug development, aiming to alter the operation of metabolism in the late stages of aging, targeting processes that are very far removed from the actual causes of aging. You can't fix a worn engine by changing the oil, and you can't repair an age-damaged human by altering metabolism so as to slow down ongoing aging.

In some areas this doesn't matter because - fortunately - there are few steps between cause and end result, and the cause itself is something that can in principle be addressed via the drug development approach, or at least where the drugs are designed compounds with very precise modes of operation. Think of age-related macular degeneration caused by a buildup of metabolic waste compounds in retinal cells. Some mainstream researchers do end up working on the direct and most useful ways to break down those compounds rather than on some much more fanciful and much less helpful scheme of altering the metabolism of retinal cells to be more resistant to a later consequence of the damage process. In this case there are few steps between aggregation of waste and dysfunction, so less room for researchers to spend a lot of time and effort on investigating later stages in the condition. It still happens, but nowhere near as much as elsewhere in the aging process.

In most other relevant areas of medical research, however, attempts at building useful implementations of aging research are not yet moving in the right direction. So while we stand at a point at which earnest development could be underway on all aspects of rejuvenation biotechnology, the basis for treatments that can repair the damage that causes aging and thus restore health to the old, and prevent the development of age-related disease, for the most part the new rhetoric emerging from the research community steps over these opportunities. Plans for realizing rejuvenation treatments exist, but much of the research community remains bound to the old incremental roadmap of drugs and metabolic manipulation to attempt to produce marginal gain in the late stages of disease: that is what they know, where they can obtain grants, and where the gatekeepers and not going to challenge you just because you are doing something different. All inertia, and very slow to change.

So researchers these days are willing to set out bold goals to include the defeat of aging and elimination of age-related disease and decline, in principle at least, but at the detail level fall back to anemic plans that cannot possibly produce meaningful results any time soon:

Physiological geroscience: targeting function to increase healthspan and achieve optimal longevity

Most nations of the world are undergoing rapid and dramatic population aging, which presents great socio-economic challenges, as well as opportunities, for individuals, families, governments and societies. The prevailing biomedical strategy for reducing the healthcare impact of population aging has been "compression of morbidity" and, more recently, to increase healthspan, both of which seek to extend the healthy period of life and delay the development of chronic diseases and disability until a brief period at the end of life. Indeed, a recently established field within biological aging research, "Geroscience", is focused on healthspan extension. Superimposed on this background are new attitudes and demand for "optimal longevity" - living long, but with good health and quality of life.

A key obstacle to achieving optimal longevity is the progressive decline in physiological function that occurs with aging, which causes functional limitations (e.g., reduced mobility) and increases the risk of chronic diseases, disability and mortality. Current efforts to increase healthspan center on slowing the fundamental biological processes of aging such as inflammation/oxidative stress, increased senescence, mitochondrial dysfunction, impaired proteostasis and reduced stress resistance. We propose that optimization of physiological function throughout the lifespan should be a major emphasis of any contemporary biomedical policy addressing global aging. Effective strategies should delay, reduce or abolish reductions in function with aging (primary prevention) and/or improve function or slow further declines in older adults with already impaired function (secondary prevention).

Healthy lifestyle practices featuring regular physical activity and ideal energy intake/diet composition represent first-line function-preserving strategies, with pharmacological agents, including existing and new pharmaceuticals and novel "nutraceutical" compounds, serving as potential complementary approaches. Future research efforts should focus on defining the temporal patterns of functional declines with aging, identifying the underlying mechanisms and modulatory factors involved, and establishing the most effective lifestyle practices and pharmacological options for maintaining function. Continuing development of effective behavioral approaches for enhancing adherence to healthy aging practices in diverse populations, and ongoing analysis of the socio-economic costs and benefits of healthspan extension will be important supporting goals.

At least the principles are aimed high: getting that said out loud on a frequent basis by researchers in the field is half the battle. The rest of it is just a matter of pointing out that the prevalent implementation strategy is terrible in comparison to one based on repair of cellular and molecular damage, such as that proposed - in detail - in the SENS outline.


Monday, January 26, 2015

Proteostasis is the desired state of correctly function in maintaining specific protein levels and an absence of damaged or misfolded proteins in cells over time. Various regulatory systems and quality control mechanisms - such as those associated with proteasomes and lysosomes - are involved in maintaining correct function in this fashion. Like other aspects of cellular biology, proteostasis is negatively impacted over the course of aging, and exceptionally long-lived species seem to have better versions of the mechanisms involved in maintaining this desirable state of continued function:

Our previous studies have shown that the liver from Naked Mole Rats (NMRs), a long-lived rodent, has increased proteasome activity and lower levels of protein ubiquitination compared to mice. This suggests that protein quality control might play a role in assuring species longevity. To determine whether enhanced proteostasis is a common mechanism in the evolution of other long-lived species, here we evaluated the major players in protein quality control including autophagy, proteasome activity, and heat shock proteins (HSPs), using skin fibroblasts from three phylogenetically-distinct pairs of short- and long-lived mammals: rodents, marsupials, and bats.

Our results indicate that in all cases, macroautophagy was significantly enhanced in the longer-lived species, both at basal level and after induction by serum starvation. Similarly, basal levels of most HSPs were elevated in all the longer-lived species. Proteasome activity was found to be increased in the long-lived rodent and marsupial but not in bats. These observations suggest that long-lived species may have superior mechanisms to ensure protein quality, and support the idea that protein homeostasis might play an important role in promoting longevity.

Monday, January 26, 2015

Researchers here show that intermittent fasting in older rats beneficially alters one narrow measure of function in the hippocampus, an area of the brain that is well-studied in connection with age-related cognitive decline:

Diminished glucocorticoid signaling is associated with an age-related decline in hippocampal functioning. In this study we demonstrate the effect of intermittent, every other day (EOD) feeding on the glucocorticoid hormone/glucocorticoid receptor (GR) system in the hippocampus of middle-aged (18-month-old) and aged (24-month-old) Wistar rats.

In aged ad libitum-fed rats, a decrease in the level of total GR and phosphorylated GR (pGR) was detected. Conversely, aged rats subjected to EOD feeding, starting from 6 months of age, showed an increase in GR and pGR levels and a higher content of hippocampal corticosterone. Furthermore, prominent nuclear staining of pGR was observed in CA1 pyramidal and dentate gyrus granule neurons of aged EOD-fed rats. These changes were accompanied by increased Sgk-1 and decreased GFAP transcription, pointing to upregulated transcriptional activity of GR. EOD feeding also induced an increase in the expression of the mineralocorticoid receptor.

Our results reveal that intermittent feeding restores impaired GR signaling in the hippocampus of aged animals by inducing rather than by stabilizing GR signaling during aging.

Tuesday, January 27, 2015

More than six years ago a research group demonstrated that autophagy can be boosted in the liver to reverse some of the age-related decline in function of that organ. Old mice were shown to have some measures of liver function little different from young mice. Science is a slow business, however. These researchers are still working their way around this area of study, and at this time there is no significant movement in the direction of translating this and other potential autophagy enhancing treatments into human therapies. This is very much the standard story when it comes to potential treatments for aging, sad to say:

Chaperone-mediated autophagy (CMA), a cellular process that contributes to protein quality control through targeting of a subset of cytosolic proteins to lysosomes for degradation, undergoes a functional decline with age. We have used a mouse model with liver-specific defective CMA to identify changes in proteostasis attributable to reduced CMA activity in this organ with age. We have found that other proteolytic systems compensate for CMA loss in young mice which helps to preserve proteostasis. However, these compensatory responses are not sufficient for protection against proteotoxicity induced by stress (oxidative stress, lipid challenges) or associated with aging.

Livers from old mice with CMA blockage exhibit altered protein homeostasis, enhanced susceptibility to oxidative stress and hepatic dysfunction manifested by a diminished ability to metabolize drugs, and a worsening of the metabolic dysregulation identified in young mice. Our study reveals that while the regulatory function of CMA cannot be compensated for in young organisms, its contribution to protein homeostasis can be handled by other proteolytic systems. However, the decline in the compensatory ability identified with age explains the more severe consequences of CMA impairment in older organisms and the contribution of CMA malfunction to the gradual decline in proteostasis and stress resistance observed during aging.

Tuesday, January 27, 2015

Immunotherapy is a promising approach for the treatment of Alzheimer's disease, in which immune cells are directed to attack amyloid aggregates or precursor proteins associated with the condition. More pertinently, this field of research could produce a successful and mature technology platform for targeting all forms of amyloid, and possibly other types of metabolic waste, that should be cleared from the body in order to remove their contributions to degenerative aging. Unfortunately progress is slow and challenging: Alzheimer's is complex, the immune system is complex, and both are incompletely understood. There continue to be many more failures than successes in the process of development.

One more recent line of work is to focus on tau aggregates rather than amyloid. There is evidence to suggest that these neurofibillary tangles are also significant in the progression of Alzheimer's disease, but again understanding of the mechanisms involved is at this point sketchy. From an engineering point of view forging ahead to build a removal mechanism in advance of full knowledge is a good approach, if it can be done given the present state of knowledge. It stands a reasonable chance of cutting straight to a viable treatment even in absence of greater knowledge, or at least shedding more light on the situation if it clears tau and yet still fails to improve the outcome for a treated individual. In this case researchers encounter a fairly typical result in this work, which is that they are floundering on unanticipated complexity, but learning as they go:

The amyloid β (Aβ)-protein and microtubule-associated protein, tau, are the major components of the amyloid plaques and neurofibrillary tangles that typify Alzheimer's disease (AD) pathology. As such both Aβ and tau have long been proposed as therapeutic targets. Immunotherapy, particularly targeting Aβ, is currently the most advanced clinical strategy for treating AD. However, several Aβ-directed clinical trials have failed, and there is concern that targeting this protein may not be useful. In contrast, there is a growing optimism that tau immunotherapy may prove more efficacious.

Here, for the first time, we studied the effects of chronic administration of an anti-tau monoclonal antibody (5E2) in amyloid precursor protein transgenic mice. For our animal model, we chose the J20 mouse line because prior studies had shown that the cognitive deficits in these mice require expression of tau. Despite the fact that 5E2 was present and active in the brains of immunized mice and that this antibody appeared to engage with extracellular tau, 5E2-treatment did not recover age-dependent spatial reference memory deficits. These results indicate that the memory impairment evident in J20 mice is unlikely to be mediated by a form of extracellular tau recognized by 5E2.

In addition to the lack of positive effect of anti-tau immunotherapy, we also documented a significant increase in mortality among J20 mice that received 5E2. Because both the J20 mice used here and tau transgenic mice used in prior tau immunotherapy trials are imperfect models of AD our results recommend extensive preclinical testing of anti-tau antibody-based therapies using multiple mouse models and a variety of different anti-tau antibodies.

Wednesday, January 28, 2015

Klotho is one of a range of longevity-associated genes identified in animal studies. You might recall that last year researchers identified a klotho variant associated with better cognitive function in humans. It didn't appear to protect against age-related decline as the researchers hoped, however. Here is more on this topic:

People who carry a variant of a gene that is associated with longevity also have larger volumes in a front part of the brain involved in planning and decision-making. The finding bolsters their previous discovery that middle-aged and older people who carry a single copy of the KLOTHO allele, called KL-VS, performed better on a wide range of cognitive tests. When they modeled KL-VS in mice, they found this strengthened the connections between neurons and enhanced learning and memory. KLOTHO codes for a protein, called klotho, which is produced in the kidney and brain and regulates many different processes in the body. About one in five people carry a single copy of KL-VS, which increases klotho levels and is associated with a longer lifespan and better heart and kidney function. A small minority, about 3 percent, carries two copies, which is associated with a shorter lifespan.

Researchers scanned the brains of 422 cognitively normal men and women aged 53 and older to see if the size of any brain area correlated with carrying one, two or no copies of the allele. They found that the KLOTHO gene variant predicted the size of a region called the right dorsolateral prefrontal cortex (rDLPFC), which is especially vulnerable to atrophy as people age. Deterioration in this area may be one reason why older people have difficulty suppressing distracting information and doing more than one thing at a time. Researchers found that the rDLPFC shrank with age in all three groups, but those with one copy of KL-VS - about a quarter of the study group - had larger volumes than either non-carriers or those with two copies.

Researchers also found that the size of the rDLPFC predicted how well the three groups performed on cognitive tests, such as working memory - the ability to keep a small amount of newly acquired information in mind - and processing speed. Both tests are considered to be good measures of the planning and decision-making functions that the rDLPFC controls. In statistical tests, the researchers concluded that the larger rDLPFC volumes seen in single copy KL-VS carriers accounted for just 12 percent of the overall effect that the variant had on the abilities tested. However, the allele may have other effects on the brain, such as increasing levels or changing the actions of the klotho protein to enhance synaptic plasticity, or the connections between neurons. In a previous experiment, they found that raising klotho in mice increased the action of a cell receptor critical to forming memories.

Wednesday, January 28, 2015

The general consensus among researchers is that over the last few centuries of increasing human life expectancy most of the early gains were due to reductions in mortality in youth, such as those caused by infectious disease, malnutrition, and the like. Over time the ongoing gains in life expectancy have shifted to occur in later life due to other forms of improvement in medicine and related technologies: present trends are as much in adult life expectancy as in life expectancy at birth. This study takes a novel approach to gain a different confirming perspective from the existing data:

Life expectancy has increased continuously for at least 150 years, due at least in part to improving life conditions for the majority of the population. A substantial part of this historical increase is due to decreases in early life mortality. In this paper we analyse the longevity of four privileged sets of adults, who have avoided childhood mortality and lived a life more similar to the modern middle class. Our analysis is focused on writers and musicians from the 17th through the 21st Centuries. We show that their average age at death increased only slightly between 1600 and 1900, but in the 20th Century increased at around 2 years/decade.

We suggest that this confirms that modern lifespan extension is driven by delay of death in older life rather than avoidance of premature death. We also show that Productive Lifespan, as measured by writing and composition outputs, has increased in parallel with overall lifespan in these groups. Increase in age of death is confirmed in a group of the minor British aristocracy, and in members of the US Congress from 1800 to 2010. We conclude that both lifespan and Productive Lifespan are increasing in the 20th and early 21st Century, and that the modern prolongation of life is the extension of productive life, and is not the addition of years of disabling illness to the end of life.

Thursday, January 29, 2015

Efforts to treat Alzheimer's disease by clearing the amyloid beta (Aβ) deposits and related precursors associated with the progression of the condition have proven to be challenging, beset with failures and complications. Wherever there is slow progress in this sort of work, there is always the question of whether the problem is just hard, or whether the whole strategy is the wrong direction. Alternative hypotheses and approaches will spring up, and there is a lot of that going on in Alzheimer's research. Still, the presence of amyloids of various forms are a hallmark of aged tissues, and they should be cleared as a part of the activity of any potential rejuvenation toolkit. The work on clearing Aβ will hopefully contribute meaningfully to the development of a general technology platform to achieve this goal, even if it turns out that Aβ removal isn't the right path for Alzheimer's treatment.

Most people nowadays are familiar with the advice that "correlation does not imply causation." However, this is difficult advice to take when considering human disease where we are unable to ethically experiment on humans without exceptionally good justification. To get that justification we have to rely on studying the effects of a disease in order to make an informed guess about what causes it. The problem with this is that distinguishing the effects of a disease from its causes can get murky.

A good example of this confusion between effects and causes is Alzheimer's disease (AD). AD is defined by the presence of "amyloid plaques" (sticky globs of a protein fragment called amyloid beta or Aβ) in the brains of people with dementia. There is lots of good evidence that Aβ can cause AD. For example, there are families that inherit early-onset forms of AD, and have mutations in the protein itself or in enzymes that process the protein into sticky fragment forms. When these mutants are expressed in mice, the mice develop some (but not all) of the symptoms of AD. Additionally, there are people who naturally produce 50% more of the precursor to Aβ in their cells due to a completely different genetic disease: individuals with trisomy-21, or Down's Syndrome. Down's syndrome is cause by an extra copy of chromosome 21, which adds a whole extra copy of the Aβ precursor. An unfortunate side effect of this disease is that the majority of individuals with trisomy 21 go on to develop dementia and AD in their 30's and 40's.

So stopping Aβ formation is a good way to stop AD, right? That has been the main approach that pharmaceutical companies have taken to treat the disease in the past. Many drugs that aim to reduce Aβ levels in a variety of different ways have been tested, and have all more or less failed to show significant effects in people with mild cognitive impairment (mild memory loss that can develop into AD) or AD. These failures have been costly, surprising, and a bit disheartening.

So why does targeting Aβ fail?

Thursday, January 29, 2015

There is a large body of evidence to link cognitive decline in aging with corresponding decline in blood vessel integrity. A variety of processes in aging contribute to failing elasticity and structural remodeling of blood vessel walls, which in turn cause deterioration in the whole cardiovascular system as it tries to adapt to changing characteristics of blood flow. It is probably the case that a fair degree of cognitive deterioration in every individual is caused by physical damage to the brain resulting from issues in the vascular system: many ongoing instances of tiny blood vessels failing, causing blockages or bleeds that harm small areas of brain tissue.

Individually these events are unnoticeable, but over time they add up, and the worse the state of your cardiovascular system the worse the impact on your brain. Thus we should expect to see strong correlations between decline in cognitive function and risk of catastrophic structural failure in the cardiovascular system. The interesting part of this ugly process is that because of the way the brain works, this distribution of physical damage results in very different levels of harm to various different aspects of cognition:

Although stroke is known to result in executive dysfunction, little is known about executive dysfunction as a risk factor for stroke. Canadian Study of Health and Aging (CSHA), a longitudinal population based study of elderly Canadians, was conducted in three waves in 1990-1991 (CSHA-1), 1995-1996 (CSHA-2), and 2001-2002 (CSHA-3). In a cross-sectional analysis on CSHA-1 subjects, any association between stroke history and cognitive function was studied. In a prospective analysis, CSHA-1 stroke-free subjects were followed to CSHA-2 to see if there was any difference in stroke incidence among subjects with different baseline cognitive status. And, in a validation study CSHA-2 stroke-free subjects were followed to CSHA-3 to see if the prospective analyses findings could be replicated.

In the cross-sectional analysis, subjects who had stroke in their history had significantly lower executive function, not memory function, scores than subjects without any stroke in their history. In the prospective and validation studies, stroke incidence was affected by neither executive nor memory scores. When the analysis was restricted to normal cognition subjects, lower executive function, not memory function, scores predicted stroke incidence, and remained significant after controlling for stroke risk factors. We found executive dysfunction to be a powerful stroke risk factor among cognitively normal subjects. Testing for executive dysfunction may help identify individuals at risk for stroke in time to prevent them.

Friday, January 30, 2015

Low-density lipoproteins (LDL cholesterol) are involved in the progressive damage to blood vessel walls that leads to atherosclerosis. The initial presence of oxidatively damaged LDL can cause a cascade of inflammation responses and further retention of LDL in the inflamed area. Macrophage cells arrive to clean up, some of which are overwhelmed by the amount of LDL to deal with and die. Their debris attracts more macrophages and changes local cell behavior, and all of this leads to a dysfunctional remodeling of the blood vessel wall and eventual growth of fatty plaques that can block the blood vessel or break off to cause a blockage elsewhere.

One source of damaged LDL is the small population of cells with dysfunctional, damaged mitochondria that exist in older people. Getting rid of those through some form of repair treatment yet to be developed would help the issue. The authors of this open access review paper propose interfering elsewhere in the process, targeting the molecular biochemistry involved in other aspects of damaged LDL behavior in the blood vessel wall:

An early sign of atherosclerosis is the accumulation of LDL-derived lipid droplets in the arterial wall. According to the widely accepted 'response-to-retention hypothesis', LDL binding to the extracellular matrix proteoglycans in the arterial intima induces hydrolytic and oxidative modifications that promote LDL aggregation and fusion. This enhances LDL uptake by the arterial macrophages and triggers a cascade of pathogenic responses that culminate in the development of atherosclerotic lesions. Hence, LDL aggregation, fusion, and lipid droplet formation are important early steps in atherogenesis.

Although the molecular mechanism of LDL retention and lipid droplet formation in the arterial subendothelium is not fully understood, it is increasingly clear that aggregation and fusion of modified LDLs prevent their exit from the arterial wall and contribute to atherogenesis. In contrast to modified LDLs, native LDLs do not readily aggregate or fuse under physiological conditions, suggesting that lipoprotein modifications drive these transitions. Many aspects of these reactions remain unclear, e.g., how do the apparently disparate chemical or physical modifications exert similar structural responses in LDL? Is there a synergy among numerous factors that influence LDL fusion? Which enzymatic or nonenzymatic modifications are particularly important in promoting or preventing LDL fusion in vivo? What are specific steps in LDL aggregation, fusion, and lipid droplet formation, and what therapeutic agents can block these pathogenic processes? These and other unanswered questions reflect the fact that atherosclerosis is a very complex chronic disease that can be influenced by an immense number of factors, many of which are not well understood.

Friday, January 30, 2015

In recent years researchers have made good progress towards a biomarker of age based on patterns of DNA methylation that change over time. The trick here is pulling out meaningful changes that are characteristically related to aging in much the same way in everyone versus the much larger set of changes that vary widely between individuals. As aging is a process of damage accumulation, some of these epigenetic changes in DNA methylation are responses to that damage, meaning that somewhere in all of this is a methodology to rapidly evaluate potential rejuvenation treatments that are based on repair of damage. That is the real significance of this ongoing field of research:

Researchers studied chemical changes to DNA that take place over a lifetime, and can help them predict an individual's age. By comparing individuals' actual ages with their predicted biological clock age, scientists saw a pattern emerging. People whose biological age was greater than their true age were more likely to die sooner than those whose biological and actual ages were the same.

Four independent studies tracked the lives of almost 5,000 older people for up to 14 years. Each person's biological age was measured from a blood sample at the outset, and participants were followed up throughout the study. Researchers found that the link between having a faster-running biological clock and early death held true even after accounting for other factors such as smoking, diabetes and cardiovascular disease.

Researchers measured each person's biological age by studying a chemical modification to DNA, known as methylation. The modification does not alter the DNA sequence, but plays an important role in biological processes and can influence how genes are turned off and on. Methylation changes can affect many genes and occur throughout a person's life. "The same results in four studies indicated a link between the biological clock and deaths from all causes. At present, it is not clear what lifestyle or genetic factors influence a person's biological age. We have several follow-up projects planned to investigate this in detail."


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