Dear Future Centenarian,
I got a recent email from Dr. Ron Klatz, co-founder of the organization that put anti-aging medicine on the map, The American Academy of Anti-Aging Medicine (A4M) https://www.a4m.com/. In fact, they are the group who coined the term “anti-aging,”
A4M is a U.S. federally registered 501(c)(3) non-profit organization comprised of over 26,000 members across the globe, including physicians (85% of their members), scientists (12%, and governmental officials (3%), all of whom collectively represent over 120 nations.
If you are seeing an anti-aging specialist, he or she was almost certainly trained and accredited by A4M. Without them, we may not have such a specialty, and many more would suffer needlessly and die prematurely.
The organization is also dedicated to educating healthcare professionals and practitioners, scientists, and members of the public on biomedical sciences, breakthrough technologies, and medical protocols through their advanced education entity: Metabolic Medical Institute (MMI).
A4M is focused on spreading awareness about innovative cutting-edge science and research, in addition to implementing treatment modalities designed to prolong the human lifespan in clinics worldwide.
No one organization has done more to make anti-aging and regenerative medicine a reality then have the physicians and scientists of the A4M.
They provide continuing medical education (CME) and training to over 65,000 physicians and health practitioners at multiple live conferences worldwide, as well as online CME education in the functional, metabolic and regenerative medical sciences.
If you don’t have an anti-aging physician, you may be able to find one in your area by going to https://www.a4m.com/find-a-doctor.html.
You can also access their healthy longevity updates by going to https://worldhealth.net/. There, you will find life-enhancing articles that you may not find in other sources.
Ron responded to last week’s Longevity News Alert by saying:
“I couldn’t agree with you more, aging in fact does suck and it sucks hard.
“Perhaps you’re familiar with the three rules of antiaging medicine number one is don’t get sick number two is don’t grow old number three is don’t die, not necessarily in that order, but you get the idea.
“In fact all the organizations in the space of anti-aging regenerative preventive medicine with the exception of Life Extension and ACAM have grown directly from A4M or its members
“Almost every one of the popular books published over the past 28 years has been from A4M members or has been copied in the whole cloth by experts in antiaging medicine who will team their expertise by attending one conference
“Thank you for your good work I enjoyed reading your reports as always. As always best wishes for a long and productive lifespan.”
Thank you Ron and…
P.S. Catch up on RAADfest 2019.
The Strategy of mTORC1 Inhibition Fails a Phase III Trial
The worst possible outcome when developing a clinical therapy is not an early failure. It is a late failure, in the final and most expensive phase III clinical trial, in which the therapy interacts with a sizable patient population, and after a great deal of time and funding have been devoted to the program.
This result is far more likely for therapies based on mechanisms that have smaller rather than larger effect sizes, and where that smaller effect size varies from individual to individual for reasons that are not well understood – something that describes all too much of the past few decades of efforts to treat age-related disease.
Unfortunately this worst case phase III failure just happened to resTORbio’s mTORC1 inhibitor RTB101, in tests of its ability to improve immune function and reduce the burden of infection in later life.
Heat Shock Proteins as a Basis for Tackling Protein Aggregation in Neurodegenerative Diseases
Neurodegenerative conditions are largely characterized by the aggregation of a few altered proteins that are prone to forming solid deposits in and around neurons.
Tissues, such as the brain, made up of long-lived cells, such as neurons, are particularly vulnerable to this sort of dysfunction, as they cannot dilute harmful protein aggregates by cell division, and dysfunctional cells are not readily destroyed and replaced.
Cells must rely upon internal quality control mechanisms such as the presence of chaperone proteins responsible for chasing down misfolded or otherwise problematic proteins, and ensuring they are refolded correctly or recycled via autophagy.
Vaccination and Antiviral Therapies Targeting CMV as an Approach to Reducing Immunosenescence
Today’s open access paper discusses possible approaches to the treatment of immunosenescence, the age-related decline in effectiveness of the immune system.
Unfortunately it is largely a tour of compensatory treatments, ways to force the cells of the immune system into greater or more useful activity without addressing any of the underlying causes of immunosenescence.
Many of these methodologies have serious side-effects, are disruptive of normal immune function and overall health, and cannot be applied for the long term. Checkpoint inhibition, or the delivery of recombinant IL-7, for example, both of which are used as short term interventions to treat cancer.
The path to actually fixing the aged immune system by addressing causes is quite different. It would involve restoring the thymus from atrophy in order to restore a more youthful pace of production of T cells. Replacing the hematopoietic stem cell population to ensure that the right balance of immune cells are produced in the bone marrow. Reversing the degeneration of lymph nodes, where immune cells coordinate. Clearing out the populations of worn, malfunctioning, and misconfigured immune cells in tissues and bloodstream.
Dogs as a Model of Human Aging
Dogs are an interesting species when it comes to the study of aging. Firstly they are much closer to human metabolism and cellular biochemistry than mice, and secondly selective breeding has generated lineages with a very wide range of sizes and life spans.
Thirdly, they occupy a good compromise position in the range of life spans, study cost, and similarity to humans. Mice live short lives, so studies are rapid and comparatively cheap, but there are sizable, important differences between mouse and human biochemistry. Humans live so long that most studies of aging are simply out of the question. Even in non-human primates that live half or less as long as we do, a study of aging and calorie restriction has lasted for decades, and few organizations can or will commit to that sort of effort.
Libella Gene Therapeutics to Run a Patient Paid Trial of Telomerase Gene Therapy
After Bioviva Science, Libella Gene Therapeutics is the second company to take a run at commercializing telomerase gene therapy treatments for human use. Telomerase is the enzyme responsible for lengthening telomeres, repeated DNA sequences at the ends of chromosomes, though it may have other roles.
Telomeres are a part of the mechanism that limits the number of times that a somatic cell can replicate. Telomeres shorten with each cell division, and when too short they trigger programmed cell death or cellular senescence followed by destruction by the immune system.
Ordinary somatic cells in humans do not express telomerase; it is only present in stem cells, which can replicate indefinitely to supply tissues with new somatic cells with long telomeres.
A Role for B Cells in the Chronic Inflammation Generated by Visceral Fat Tissue
Much of the long-term harm caused by excess visceral fat tissue is due to raised levels of chronic inflammation, the inappropriate over-activation of the immune system characteristic of both obesity and aging.
Chronic inflammation accelerates the progression of near all of the common age-related conditions. There are numerous mechanisms via which fat tissue rouses an immune response: cellular debris that triggers immune cells into action; generation of excessive numbers of senescent cells; inappropriate signaling from fat cells that mimics the response to infection; infiltration of inflammatory macrophages into fat tissue; and so forth.
A Mechanism by which Cellular Senescence Drives Pulmonary Fibrosis
The lingering senescent cells that accumulate with age are an important contributing cause of degenerative aging. If nothing else, their secretions generate a significant fraction of the chronic inflammation of aging, disrupting tissue function and immune function.
Chronic inflammation is in turn well known to accelerate all of the most common age-related conditions. Fibrosis is a consequence of dysfunctional tissue maintenance and regeneration, in which scar-like deposits form, degrading tissue function.
There is good evidence for fibrotic diseases, such as those of the lung, kidney, and heart, to be driven in large part by the presence of senescent cells. This is good news for patients, as while there is little that can be done to treat these conditions in the practice of medicine at the present time, senolytic therapies to clear senescent cells may well help to turn back fibrosis.
There is no consensus in science that is so strong as to have no heretics. So here we have an interview with a naysayer on the matter of senolytic treatments, who argues that the loss of senescent cells in aged tissues will cause more harm to long-term health than the damage they will do by remaining.
To be clear, I think this to be a ridiculous argument given the present evidence. To make it one has to declare the existing results showing extension of healthy life span in mice to be something other than credible data, which just isn’t the case.
Further, it seems shaky on theoretical grounds to suggest that removal of something like 1% of cells will put onerous stress on the remaining 99%, particularly given that the 1% were contributing to declining stem cell activity via inflammatory signaling.
All told, it is hard to take seriously the idea that loss of senescent cells can possibly produce greater degrees of dysfunction in tissue than is caused by the inflammatory signaling of senescent cells.
Targeting ?-Synuclein in the Gut to Turn Back the Progression of Parkinson’s Disease
Like most neurodegenerative conditions, Parkinson’s disease is driven in large part by the pathological aggregation of misfolded proteins, in this case ?-synuclein.
These solid deposits of protein spread from cell to cell, and are accompanied by a surrounding halo of harmful biochemical interactions. There is evidence for the protein aggregation of Parkinson’s disease to start in the gut and then spread to the brain.
You might look at a recent paper that discusses whether or not we should consider Parkinson’s to be two diseases with a similar outcome, one in which the ?-synuclein aggregation originates in the gut, and the other in which it originates in the brain. In the research noted here, scientists are following the gut origin hypothesis and targeting ?-synuclein there in order to slow or reverse the progression of Parkinson’s disease.
Greater Physical Fitness Correlates with Lower Risk of Dementia
It is well established that exercise and physical fitness correlate well with reduced incidence of all of the common age-related diseases, and reduced mortality risk.
It is hard to establish causation from the contents of human epidemiological databases, but the analogous animal studies convincingly demonstrate that exercise improves health. There is no reason to expect humans to be all that different in this matter. Here, researchers show that, much as expected, greater fitness correlates with reduced risk of dementia. Of note, patients that improved their fitness over the years of later life exhibited reduced disease risk and improved life expectancy.
7-Ketocholesterol as a Contributing Cause of Multiple Age-Related Diseases
One noteworthy difference between the biochemistry of young and old individuals is a greater presence of oxidative molecules, resulting from dysfunctional cells, inflammatory processes, and other issues.
As a consequence, there are also many more oxidized molecules, changed from their original structure and now either broken or actively harmful. Cells clear out this sort of oxidative damage constantly, and are quite efficient at this sort of maintenance until levels of oxidization become high, but they nonetheless struggle with some particularly toxic or resilient oxidized molecules, even in smaller amounts.
A good example of the type is 7-ketocholesterol, a form of oxidized cholesterol. It is primarily understood as an important contributing cause of atherosclerosis via its detrimental effects on the macrophages responsible for clearing lipids from blood vessel walls, but there is evidence for it to contribute to other age-related conditions as well.
The Aged Adaptive Immune System is Strange
The adaptive immune system of an older person is a very different beast in comparison to that of the younger self. It has lost the supply of new T cells due to atrophy of the thymus, and the remaining population of T cells becomes ever more damaged, misconfigured, strange, and different.
The immune system as a whole is complex enough to still be hiding many unexplored details, even in this era of biotechnology. Here, researchers outline a novel discovery in the immune function of supercentenarians.
It seems that at very advanced ages, some T cells start to undertake radical shifts in function in order to compensate somewhat for the growing lack of capacity. It remains to be seen whether or not this only occurs to a significant degree in a minority of the population, and is thus a feature of supercentenarians because it increases the odds of survival.
Evidence for Inflammation to Drive Tau Pathology in Alzheimer’s Disease
Researchers here provide evidence for the aggregation of altered forms of tau protein in the aging brain, and the resulting death of neurons, to be driven by chronic inflammation.
This is good news if true, given recent work carried out in animal models of tauopathy, in which clearance of inflammatory, senescent glial cells in the brain was achieved via the use of senolytic drugs. The result was a marked reduction in both inflammation and tau pathology.
To the degree that senescent cells in the brain prove to be the major cause of the chronic inflammation of aging and neurodegenerative conditions, it may well turn out that senolytic drugs will do a great deal for Alzheimer’s patients. Since the senolytic drug dasatinib is off-patent, crosses the blood brain barrier, and is well tested for human use, trials could in principle begin just as soon as a sponsoring organization emerges and chooses to start.
The Dog Aging Project Forges Ahead with a Large Study
As noted here by the Life Extension Advocacy Foundation, the Dog Aging Project researchers are moving ahead with a large study of companion animals. While much of the study is observational, a sizable cohort will be treated with the mTOR inhibitor rapamycin.
Dogs are much closer to humans than mice, so it will be interesting to see what results. Given what is known of the way in which stress response upregulation behaves in different species, we would expect to see similar effects on cellular biochemistry – such as upregulation of autophagy – but smaller relative gains in life span in dogs versus mice.
Short-lived species have a much greater plasticity of life span in response to environmental circumstances than longer-lived species, something that probably has its roots in adaptation to seasonal famine. A mouse must extend its reproductive life span by a larger proportion than a dog or a human in order to pass through a famine and carry on its lineage on the other side.