AGINGSCIENCES™ – Anti-Aging Firewalls™

Is increasing longevity be good for the society or does it pose a burden on younger people?  I outline where I am on this issue here because it has a lot to do with what motivates me to continue generating this Blog and update my treatise AntiAging Firewalls – the Science and Technology of Longevity.

Let me start by stressing that the intent of life extension as I am pursuing it is to extend life in a condition of health permitting constructive contribution to society.   It is not to squeeze one or two more unproductive years out at the ends of lives.  I am not advocating life extension if the resulting quality of life precludes continuing social contribution.  I am not for keeping people alive as living vegetables in hospital or nursing home beds.  I am also not very interested in extending the lives of older people who have given up all hope of contributing to others and who are basically waiting to die.  It is no secret that a disproportionate share of medical costs in advanced society like ours are for advanced surgeries and expensive drugs for older people, treatments that are very limited in their effectiveness against age-related diseases.  I am arguing not for such treatments but rather for measures that postpone or eliminate the typical diseases of aging.  The result should be more productive years and hopefully a larger average ratio of productive years to unproductive years of life.

Now, let’s look at some of the key arguments against extending longevity.

The argument from evolution is perhaps the most respectable.  It goes like this:  Each species, humans included, has evolved characteristic life-spans designed to optimize the survival of that species taking into account resource limitations, a need for protection against predators and diseases, and environmental conditions.  Scarce resources need to be devoted to providing for the young and raising new generations and fighting off predators and diseases during the years of rearing the young.  According to this argument, need for individual survival diminishes after child-rearing years.  Younger animals are stronger and can better fight off predators and diseases than older ones. From the viewpoint of the human species, then, resources are better devoted to raising and protecting children than to keeping old people around, people who are no longer part of the reproductive-child-rearing cycle.  According to this argument, finding means to extend lives of old people leads to a misallocation of resources that is counter to survival of the species. 

The problem with this argument is that it takes biological evolution into account but not social evolution.  The argument  does not take into account the ever-increasing complexity of our society, the ever-increasing requirement for education that is necessary to function well in society, the ever-increasing cost of rearing young including education, the increase in the time required for young people to become fully functional in society, and the need for people to spend more years working to cover the ever-growing costs for educating their young.  As social evolution advances at an exponentially increasing rate and society continues to become more complex, there is an ever-increasing need for people to draw on vast resources of information, deep knowledge and wisdom to survive and advance the society.  The time required for basic education continues to grow and continuing education becomes a lifelong necessity.   Longer life spans therefore serve the need of social evolution by increasing mobilization of knowledge and wisdom. 

In fact, social evolution has been working hard to extend our longevity in recent times.  A few hundred years ago people typically died before 40.  Now, life expectancy has roughly doubled, to about 78 for US males and 80 for females.  All the other typical age-marking numbers have also roughly doubled.  Once young males could join their fathers as hunters or warriors or farmers or artisans at the age of 15 and start fully contributing to society shortly thereafter.  About twice as much time (30 years) is now required in an advanced society for a male to become a doctor or lawyer or physicist, to become fully engaged in his profession, to get married and have children.  Females used to start having babies when they were biologically capable, around 15.  Now for educated Western women, the age is roughly 30.  The investment required for rearing a child has become enormous – $300,000 – $500,000 or more for a thirty year period when including the cost of preparatory education.  All this change has happened in less than 400 years.  The key thing to focus on is that the number of productive years – the years between completion of education and retirement – has doubled too. Instead of 20 good working years now the average is more like 40. 

So, social evolution requires longer life spans because people have to become ever more sophisticated to accommodate to ever more-complex social conditions.  Now as social evolution continues to accelerate at an exponential pace, it is appropriate that life spans also become extended at an accelerating rate.  That is what my work is about.

My main point is this:  as society becomes exponentially more complex, so a need arises for exponential growth in life expectancy.  Life extension is not about older people surviving unproductively longer in retirement communities in Florida or nursing homes.  It is about keeping an increasingly complex society workable.

A simplistic variant of the argument from evolution is to say extending lives is not natural.  If nature or God wanted us to live to 150 or beyond, he or she would have set it up that way, the argument goes.  My response is: who says what is natural?  From the viewpoint of the year 1600, living lives as long as the ones we enjoy now would have been seen as highly unnatural. 

Another argument against life extension is the burden on the young argument.  It is another variant of the argument from evolution stating that extending the lives of older people will lead to more and more unproductive older people, an unfair burden on the young people.  My response to this is that there should be no such burden.  The young, by virtue of their requirement for a long and expensive period of rearing and education are already a burden on their working parents – those in their productive years.  I am arguing for further extending the productive years so as to give more time for amortizing the investments in the young and minimizing the burden for those in their productive years due to having to take care of the young as well as the debilitated and unproductive old.

Another argument against life extension is that a society consisting of much older people will lack vibrancy, stress conformity and be uncompetitive compared with societies consisting of younger people.  The opposite is true.  In most countries in Africa and the Middle East where the population has recently exploded, the average age is now under 25.  Educational level per capita is minimal, the societies and their people cannot compete on the world stage, and there appears to be a chronic condition of poverty and social hopelessness.  In those countries lives are not seen to be worth much and average life spans are relatively short.  In advanced Western countries where there is large investments in education and life spans are long, lives are worth a lot.  It just takes a lot of years for people to come up to speed so they can compete in the world economy today.

The final argument against life extension I will deal with here is it will drive our social security and retirement systems broke.  True, if people live longer and longer on the average and we don’t adjust our retirement ages and expectations for retirement upwards,  We need to readjust our thinking about older people working.  I am one of possibly a million people around 80 who is perfectly capable of handling a full-time job.  As it happens to be, I am working 50-70 hours a week, self-employed and basically concerned with longevity science.  However, virtually no businesses, government agencies or health institutions are willing to employ people my age in regular jobs.  Twenty five years ago, 60 was the mandatory retirement age.  Now it is 65 and possibly going on 70.  As longevity increases and larger number of people are taking anti-aging measures, we need to change the culture so these people are not automatically thrown out of the work force when they reach an arbitrary chronological age.

Here is my vision:  A society where people live longer and more healthily, where the average period of suffering from end-of-life disability grows shorter and shorter compared to the total, where the knowledge and wisdom of older people is put fully to work, and where longevity translates into productivity that helps all. 

Exotic genetic diseases often provide important clues for the aging process, and I have previously discussed implications of Hutchinson-Gilford progeria and Werner Syndrome in this Blog.  This time, a research item on Hoyeraal-Hreidarsson Syndrome(HHS)  came to my attention.  “Hoyeraal-Hreidarsson syndrome is a multisystem disorder affecting males and is characterized by aplastic anemia, immunodeficiency, microcephaly, cerebellar hypoplasia, and growth retardation. HHS is a severe variant of dyskeratosis congenita(ref).”(ref).  HHS is “mainly characterized by telomerase deficiency, accelerated telomere shortening, impaired cell proliferation, bone marrow failure, and immunodeficiency(ref).”  Telomere shortening and damage is the 12^th theory of aging covered in my Anti-Aging Firewalls Treatise.

The key conclusion of the new research is “Altogether, these results suggest that the primary defect in these patients lies in the telomere structure, rather than length. We postulate that this defect hinders the access of telomerase to telomeres, thus causing accelerated telomere shortening in blood cells that rely on telomerase to replenish their telomeres. In addition, it activates the DDR (DNA damage response) and impairs cell proliferation, even in cells with normal telomere length such as fibroblasts. This work demonstrates a telomere length-independent pathway that contributes to a telomere dysfunction disease(ref).”  The problem in the case of HHS is apparently due to diminished 3′ overhangs which are part of telomeric DNA, that is, defective telomere caps.  Telomerase works by adding telomeric repeats off of the 3” overhangs and, if the overhangs are not normal, cannot do its job of extending telomeres. The researchers tracked the problem down to mutations in the telomerase subunits and in the Shelterin component Tin2.  Shelterin is a protein complex that is essential for shaping and protecting human telomeres.  It has six components: TRF1, TRF2, TIN2, Rap1, TPP1, and POT1.  Shelterin is important for enabling cells to distinguish telomeres from sites of DNA damage.

The study demonstrates the complexity involved in telomerase activation and that many pathways can contribute to either telomere extension or shortening. The devil is in the details.  The results are related to those posted in previous blog entries: More research progress on telomerase, and Stem cells, telomeres and telomerase and DNA repair.

I searched the news this morning for items related to stem cell disease therapies.  I found over 60 items.  My impression is that the situation is a bit like commercial aviation was in 1926: everybody is talking about it, visionaries are sure it will be a very big thing, there is a lot of disconnected activity going on all over the place, and safety is a big question.  And, the regulatory rules-of-the-game still have to be worked out.  Most potential stem cell therapies are still far from being part of mainline medicine and it is difficult to make sense about where things stand.   

The most practiced approach to stem cell therapy is to take autologous (a patient’s own) mesenchymal or hematopoietic stem cells from the patient’s bone marrow, grow the numbers of them in culture, and reintroduce them into the body in a way that hopefully leads to cure of a diseases or organ regeneration.  Use of a patient’s own stem cells avoids problems of immune system rejection encountered when other people’s stem cells are used.  Mesenchymal stem cells (MSCs) “ – are multipotent stem cells that can differentiate into a variety of cell types. Cell types that MSCs have been shown to differentiate into in vitro or in vivo include osteoblasts, chondrocytes, myocytes, adipocytes, and, beta-pancreatic islets cells(ref).”  Hematopoietic stem cells (HSCs)  are also multipotent cells that can differentiate into “all of the blood cell types including myeloid (monocytes and macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes/platelets, dendritic cells), and lymphoid lineages (T-cells, B-cells, NK-cells)(ref).” 

There are also other approaches, such as using other autologous stem cells (like nerve or hair stem cells), stem cells transplanted from other people, fetal stem cells, amniotic stem cells, and stem cells made by reprogramming ordinary cells.  But I am mainly not concerned with those here. 

The technology of harvesting stem cells from bone marrow is well worked out.  The challenge is to re-introduce the cells in the right place under the right conditions so that they produce the intended results.  Whether stem cells differentiate and what cells stem cells differentiate into depends very much on local inter-cellular signaling and in most cases that signaling is not well understood.  Here is a sampling of scattered items intended to give a flavor of what is happening: 

·        A few “classical” stem cell therapies based on using other people’s cells are in routine use today, such as for treatment of leukemia(ref).

·        The FDA apparently wants to subject new stem cell therapies to the same approval procedures required of new drugs.  This means they must pass through a controlled bureaucratic process that is likely to cost tens or hundreds of millions of dollars and require seven to ten years of clinical trials for completion.

·          A group of US doctorsis challenging that position(ref).  They claim that introducing a patient’s own cells back into the body is very different than introducing a foreign drug substance.  Accusations have been made that the FDA is killing approval of stem cell therapies by slowing down autologous stem cell transplants and therefore killing patients(ref).  How this will play out on the political and medical stages is difficult to predict.

·        Private clinics and hospitals have set up stem cell therapy shops in other countries where regulations permit.   This article in Forbes outlines overseas stem cell treatment options for Parkinson’s Disease, Alzheimer’s Disease, Multiple Sclerosis, Cardiovascular Disease, and Diabetes in countries such as China, Costa Rica, Ukraine, Republic of Georgia,  Russia, India, Germany, Israel, Mexico, Thailand, Argentina, Panama, Singapore, the Dominican Republic and countries in  Eastern Europe.  Costs typically range from $10,000 to $35,000. An example of a private stem cell clinic is the Xell Center in Germany. Xell only does autologous transplants, offers treatments for a variety of conditions, and claims there is no associated tumor risk.

 ·        Pet and animal stem cell therapy is starting to thrive.  Treating dogs for arthritis and horses for orthopedic injuries seem to be favorites.(ref)(ref).

·        A small Phase II European study suggests that autologous stem cell therapy is effective in treating congestive heart disease(ref).

·        NIH has launched a study of hematopoietic stem cell transplantation for severe, treatment-resistant lupus(ref).  This approach may show promise for this formerly intractable disease.  The idea is to reboot one’s immune system(ref).

·        One branch of autologous stem cell therapy research involves genetically modifying the stem cells before they are re-inserted.  See the recent post on this blog Trojan horse stem cells might offer an important new cancer therapy.  Stem cell transplants can be used to transfer new genes into patients, for example to protect them from some of the negative effects of chemotherapy treatments(ref).

·        Based on work with 9 patients, it appears that autologous Mesenchymal stem cells might be employed as part of a process to cure painful chronic fingertip ulcers experienced by many patients with scleroderma(ref).  A cultured stem cell mixture is externally applied to the would along with bioengineered skin.

·        A search of the website ClinicalTrials.gov using the search term stem cells retrieved 2572 studies, a few completed, some ongoing and many now recruiting.  Of course not all of these involve use of autologous cells. The disease conditions addressed cover nearly every area of medicine.

·        Reports of failures and in some cases deaths resulting from stem cell therapies continue to create doubts about them in the minds of many medical professionals.  For example, in one case of using human fetal stem cells, brain and spine tumors emerged(ref).  Some researchers feel the risks of such things happening are less when autologous transplants used.  Also, stem cell clinical trials have been discontinued for safety reasons.  Just a few days ago, Aastrom Biosciences Inc. suspended a clinical trial after received a report that a patient died some time after treatment with autologous stem cells for congestive heart failure. It is not known whether the patient’s death is related to the treatment(ref). The FDA is placing the trial on hold pending an investigation.

If all of this leaves you a bit unclear about where things really are, please be comforted by knowing that I am unclear too.  I was that way back in 1969 when I was trying to keep up with developments in the computer field.  So, perhaps the situation is not so bad.  It can only bring good news for longevity.

I have written previously on the difference between brute-force cancer therapies and highly focused new- generation ones in the pipeline.  See the post From four-pound hammer to smart molecules – on cancer treatments.  Radiation therapy and most forms of chemotherapy kill normal cells along with cancer cells – like the four-pound hammer approach to swatting flies.  Suppose there were 1. a protein that would selectively kill cancer cells but be harmless to normal cells, and  2.  safe and easy ways existed  for triggering the action of that protein in cancer cells.  The comment made yesterday by Res in response to my post Trojan-horse stem cells might offer an important new cancer therapy set me on the trail of TRAIL which appears to be just such a protein.  TRAIL stand for tumor necrosis factor–related apoptosis-inducing ligand.   TRAIL is also called APO-2L and consists of 281 amino acids.   As pointed out earlier, “TRAIL induces apoptosis via death receptors (DR4 and DR5) in a wide variety of tumor cells but not in normal cells(ref).”    “ — TRAIL delivery in anticancer experiments does not result in any deleterious effect on normal cells. Therefore, many oncologists predict that TRAIL has the potential to be developed as an anticancer drug that selectively restricts primary as well as metastatic tumours(ref)” 

TRAIL appears to be the mechanism of anti-cancer action of the potential stem cell therapy mentioned in the previous post, where mesenchymal stem cells are loaded with TRAIL warheads and act as missiles that home in on cancer cells.  Certain of the supplements in the Susceptibility to Cancer Firewall, particularly curcumin(ref), resveratrol(ref) and green tea, owe at least some of their anti-cancer effects to the operation of TRAIL.  In the case of prostate and other cancers, curcumin inhibits the activation of NF-kappaB which makes them more sensitive to apoptosis by TRAIL(ref,ref,ref). Resveratrol appears to have the same effect in certain tumors(ref)(ref). The same appears to be true for EGCG, the major active constituent of green tea(ref).   I speculate that other plant-derived polyphenols in the anti-cancer firewall might have similar effects, enhancing TRAIL-mediated death receptor activation in cancer cells. Possibly, most of the 39 inhibitors of NF-kappaB in the firewall might work to empower TRAIL and fight cancers in the same way. 

It appears that combating cancers via TRAIL is now a major approach under research investigation.  However, some cancer cells offer resistance to TRAIL-induced death receptor apoptosis.  Using TRAIL with another anti-cancer therapy might be helpful in such cases.  Velcade, a proteasome inhibitor, sensitizes cancer cells to TRAIL.  It has been suggested that TRAIL might be combined with the anti-cancer drug Velcade to achieve a synergistic effect(ref). 

The Anti-Aging Firewalls treatise is now a year old.  It is sometimes updated weekly, sometimes daily and has undergone several major revisions.  As expected when I first published the treatise, it is now very different from the original.  The latest version embodies a new section ADDITIONAL CANDIDATE THEORIES OF AGING that integrates material formally published on this blog with existing and other new material.  Now there are six additional candidate theories of aging in addition to the original 14 theories – views of what might drive aging in most cases suggesting possible intervention strategies.   I intend to continue reporting on relevant topics and news here in this blog and to updating and maintaining the treatise as important new developments come to my attention.  Again, my intention is that the treatise will continue to be a comprehensive and definitive document on what science knows about aging and on corresponding science-based anti-aging interventions.  Achieving this may become harder and harder as the pace of progress continues to pick up, but for the present I am enjoying the challenge this task poses.

There is a constant stream of news stories on new possible approaches to curing cancers.  Cancer research institutions love to see these.  They help to impress the funding sources.  But most of these press releases describe incremental progress on existing therapeutic approaches.  It is rare to see a news story on a basically new and promising way to control  or cure cancers.  I think such a news story may have appeared today.  (See ref and ref). 

The therapeutic concept is simple and based on two observations.  The first observation is that for some reason mesenchymal stem cells (MSCs which are normally found in bone marrow) circulating in the body seek out cancer cells.  I conjecture that this is because cancers excrete signaling molecules that cause the circulating MSCs to home in on them, a strategy cancers use to achieve rapid growth(ref). The second observation is that it is possible to attach a payload molecule to mesenchymal stem cells which cause them to kill cancer cells but not normal cells, a molecule called TRAIL (A TNF-related apoptosis-inducing ligand in case you wanted to know).  “TRAIL induces apoptosis via death receptors (DR4 and DR5) in a wide variety of tumor cells but not in normal cells(ref).”  

The new research involves genetically engineering mesenchymal stem cells to be “Trojan horses” carrying TRAIL.  The stem cells seek out cancer cells and the TRAIL kills them.  The approach is reported to work in-vitro for a number of different cancers and in-vivo in a mouse model of breast cancer.  “In culture, the stem cells caused lung, squamous, breast and cervical cancer cells to die (all p< 0.01), even at low stem cell/tumor cell ratios (1:16). In mice, the researchers showed that the stem cells could reduce the growth of subcutaneous breast tumors by approximately 80 percent (p< .0001). The stem cells could also be injected intravenously as therapy for mice with lung metastases and could eliminate lung metastases in 38 percent of mice compared to control mice, all of which still had metastases (p=0.03)(ref).”  

It will probably take a few years before this cancer therapy approach is tried out in humans but it sounds promising to me.  Unlike blunderbus chemotherapy approaches the approach would be highly targeted, first in that the treated stem cells specifically seek out cancer cells, and second in that the payload kills only cancer cells not normal ones. Result should be minimal collateral damage. Most likely a patient’s own mesenchymal stem cells would be used to avoid any problem of immune system rejection so the therapy would be minimally problematic or toxic for the patient. 

I discussed the general topic of individual DNA testing in an earlier post.  There is an important twist that I cover here.  Low-cost consumer-oriented genetic testing is making personal genomic information available to individuals in a way not intermediated by the medical or any other professional establishment.  The result is an unprecedented opportunity for individuals to take more responsibility for their wellbeing and longevity.  However, there are certain associated problems and hazards. 

Up until recently, genetic testing was available through laboratories that mainly service professionals – medical people, crime specialists and genetic counselors for example.  If you had a genetic test it was ordered for you with a specific purpose in mind by somebody who also interpreted the results.  Now there are a number of direct-to-consumer web-based genetic testing services.  A person goes on a website, orders a test, receives a kit and sends a sample in.  He or she gets the result with no professional involved. At that point the person may or may not research the meaning of what was discovered further, may or may not decide to act on the results, and may or may not decide to consult a professional. The person may or may not share the result with his or her primary physician or spouse.

I have mentioned that a number of consumer companies do single-purpose tests, such as paternity testing or testing for HIV.  There is a growing number of companies that simultaneously scan for a number of possible disease or other susceptibilities.

A much-discussed low-cost example example company is 23andme. For $399 the company sends you a kit.  You spit into a tube and send it back to the 23andme lab and in 6-8 weeks the results are posted to a secure online site.  The test looks at genes related to 114 disease conditions and traits, a list that grows in time.  Examples of the conditions tested for include Parkinson’s Disease, Prostate Cancer, Psoriasis, Resistance to HIV/AIDS, Rheumatoid Arthritis, Sickle Cell Anemia & Malaria Resistance, Type 1 Diabetes and Type 2 Diabetes.  For each condition tested, certain basic information is provided.   The results provide an estimate of whether the genetic risk for a given condition is higher or lower than average, and background information on the condition and a list of counselors, links and condition-related support groups in the customer’s area.  The results for any given condition are based on one or several genetic markers, six of them in the case of rheumatoid arthritis.  Specific examples can be seen by clicking on any of the links just listed.  The service is an example of genotyping (looking at SNPs, sequence variations within a single nucleotide) to determine certain genetic variants a person possesses, which is very different than sequencing an individual’s entire genome. 23andme also offers updated clinical reports and research reports on the diseases, traits and conditions covered. 

Navigenics (www.navigenics.com) is another company in the consumer genomics game. It offers two levels of testing, one for $499 and its most comprehensive service for $2,499.  Both services suggest individual’s genetic predisposition to the common health conditions covered and “information and support to help you prevent, detect or diagnose them early,” including limited access to genetic counseling. Decodeme is another company in the consumer-oriented testing game offering a “cardiovascular” scan for $199 and charging $985 for its “complete scan” which scans over a million genetic variations for 38 conditions.  GeneDX is one of several specialized companies that scans for rare hereditary diseases.  The most comprehensive service seems to be Knome which offers complete genome sequencing looking at all 3 billion base pairs in the human genome.  “Each individual is assigned a complete team of bioinformaticians, geneticists and clinicians to conduct a comprehensive analysis of your complete genome.” The services are customized.  Costs are unpublished but I would guess they could range up to $100,000.

Heralding the emergence of consumer genomic testing as a highly competitive industry, a trade show for the industry is scheduled, The Consumer Genetics Show, Boston, Hynes Convention Center: June 9 – 11, 2009.

The hope of widespread consumer genetic screening is that individuals can identify disease susceptibilities and take appropriate actions.   If a person knows he has a susceptibility to cardiovascular disease or diabetes or he or she may make dietary and lifestyle changes to reduce the probability of the disease emerging.  People with susceptibility to arthritis may elect to take additional anti-inflammatory supplements, for example.  The individual is empowered to exercise preventative medicine on a personal level, clearly an important factor for enhancing longevity.  Further, if a couple does such testing before having children, they could possibly spot common negative inheritable traits that could emerge in an offspring.

Some genetic counselors are dubious about massive consumer genetic testing.  Reasons are 1. The state of research knowledge linking genetic markers to specific diseases is still very primitive and sketchy.  For the disease susceptibilities that are multigenic (involving multiple genes), in most cases the causative gene relationships are yet to be identified.  Scientific and medical researchers and practitioners have not agreed on appropriate diagnostic genetic biomarkers for most such conditions.  Further some important known biomarkers are proprietary and patented and can only be used by the company owning the rights to use them.  It is unclear who has the best biomarkers.  2.  Individuals are apt to misinterpret genetic results, either missing clues or suffering unnecessarily from worrying about a disease susceptibility that will never be realized.  For many of the conditions tested there is insufficient research evidence to justify firm conclusions.  Results need to be interpreted along with other important information including family history, health history, current health, environment, lifestyle, etc.  Providing such context and guidance to action is the role of genetic counselors.  I have heard one such counselor say the 23andme tests “only have entertainment value and it would be dangerous to read anything else into them.”

In all fairness, all of the consumer genetic testing services provide optional or built-in linkages to genetic counselors and attempt to identify the reliability of their findings in terms of the current state of research.  They also strive to keep up with such research and adjust their tests accordingly.  I expect that as time progresses we will have better and better underlying research to back up test result conclusions and that genomic consumer testing will become more and more commonplace.  Competition and lower-cost technology is likely to cause the tests to become ever cheaper, more comprehensive and cost-effective.  The cost of gene testing is rapidly dropping according to a variant of Moore’s Law.  (See the post on this Blog about the factors that drive Giuliano’s Law).  The latest generation of microfluidic gene-analysis chips are little bigger than a flake of dandruff and are getting down to costing less than a bottle of shampoo.  From $10, 000 down to $399 for a set of tests was a big drop.  The next drop may be down to $69.99.  And who knows if any bottom is in sight after that. 

There is a message here to medical and health professionals: you better get out there and learn about the gene tests and what they can mean if you want to maintain your creditability with your patients.  The same is true for longevity research, by the way. 

I published the first online version of the Anti-Aging Firewalls treatise a year ago and started this blog about six months ago.  A lot has happened on the longevity front during the period.  There have been 78 blog posts and the treatise has been updated dozens of times.  See Anti-Aging Firewalls V1.9 state of progress for a progress report as of two months ago.  The present version of the treatise is significantly expanded, corrected and far more comprehensive than the original.  Nonetheless a number of important developments have been reported in this blog and are not yet sufficiently covered in the treatise itself.  For me, it is important that the treatise at any time offers comprehensive coverage of what science knows about aging and what can be done about it.  Therefore I plan to focus my efforts during the next several days to bringing the treatise up to date.  You may not hear much from me here during that time.

I do want to share one thought from what I am writing, however.  There are the 14 theories of aging listed in the treatise and six additional candidate theories described in this blog that need to be described also in the treatise even though they don’t qualify as full aging theories yet.  They are Incorrect protein folding, Accumulation of progerin, Gene mutations leading to hellicase abnormalities, Aberrant mTOR signalling, The hypoxic response and Epigenomic changes in DNA methylation.  

Regarding these 20 theories or others that might come up, a single key theory of aging may not exist.  There are lots of biomolecular actions and genetic pathways that can lead to accelerated aging, and it appears there are also several that can delay aging at least somewhat.  Some may be more fundamental than others.  But it may well be that there is no one master theory or mechanism of aging that drives all the others.  It may be that we are looking at a large system of interacting feedback loops in which all the mechanisms of aging work together affecting each other in multiple ways.  All are primary. 

Think of a mechanical wrist watch.  It contains numerous gears, wheels, cogs and bearings.  Which is the main gear or wheel or bearing, the key component for operation of the watch?  Wrong question.  They are almost all needed.  Taking out or breaking almost any gear or cog or wheel or bearing will stop the watch or make it run screwy.  If you want a healthy functioning watch it is important that all the parts be in good shape and well-aligned with each other.  Same for us.

We have heard about so-called “longevity genes” that are over a billion years old.   A number of these in humans (15 or so) are also found in primitive species such as nematode roundworms (c-elegans), and are associated with the target of rapamycin (TOR) signaling pathway.  The mammalian counterpart of TOR is known as mTOR. My purpose here is to lay out a plain-language overview of TOR and mTOR-related longevity research and see what light this research might throw on the theories of aging in my Anti-Aging Firewalls treatise.   It turns out that the new findings are relevant to at least the Oxidative damage and Mitochondrial damage theories of aging.

Mammalian target of rapamycin (mTOR) is a protein encoded in humans by the FRAP1 gene.  As the name suggests, mTOR is targeted by the immunosuppressive drug rapamycin, a drug used clinically to treat graft rejection and restenosis and being tested as a treatment for autoimmune diseases.   “The mTOR pathway integrates signals from nutrients, energy status and growth factors to regulate many processes, including autophagy, ribosome biogenesis and metabolism(ref, ref).”   The mTOR pathway is “a central controller of cellular and organism growth that integrates nutrient and hormonal signals, and regulates diverse cellular processes(ref).”

The mTOR pathway plays important role in diseases.  Recent studies link mTOR to several age-related human diseases including diabetes, cancer, obesity, atherosclerosis, nephrotoxicity, cardiovascular diseases and neurological disorders. Inhibiting mTOR using rapamycin or derivative drugs offers a promising therapeutic approach for dealing with several diseases and cancer lines(ref,ref,ref).  “Dysregulation of mTOR signaling occurs in diverse human tumours, and can confer higher susceptibility to inhibitors of mTOR(ref).” 

Inhibiting mTOR may also offer an approach to enhancing human longevity.  Decreasing TOR signaling can extend the lifespans of flies and worms.  It does this by upregulation of mitochondrial gene expression resulting in decreased production of reactive oxygen species. “Reduced TOR Signaling Extends Chronological Life Span via Increased Respiration and Upregulation of Mitochondrial Gene Expression(ref)”  With respect to humans, much of the machinery of TOR signaling found in more primitive species is conserved.   “Recent data have also revealed that mTOR is involved in the regulation of lifespan and in age-related diseases(ref).” TOR also plays a role in the longevity-producing effects of calorie restriction(ref).

There are some tantalizing hints about how the mTOR pathway may relate to the other theories of aging.  For example, there are complex feedback interactions between the pathways involving NF-kappaB, mTOR and PI3K-Akt related to both treatment of cancers and longevity(ref).  A cancer treatment leads to simultaneous down-regulation of mTOR and telomerase activity in cancer cells(ref).  Inhibiting mTOR via rapamycin resulted in impairment of pluripotency and prevention of adult stem cell differentiation, among other effects(ref). As far as I can tell, however, discussions of human life extension via mTOR inhibition are at this point conjectural.  Based on what I have seen in fact, there have been no experiments so far to try mTOR inhibition for life extension on any mammals, even mice.  There are plenty of adverse effects associated with rapamycin, some possibly quite serious.  These are enough to throw cold water on any idea of healthy people using this substance in an effort to enhance their longevity

Does the mTOR story lend light on whether mitochondrial activity is more important than cell signaling or protection against oxidation damage for determining longevity?  The story actually lends light on the fact that this is the wrong kind of question to ask “Such notions are slowly giving way to a more nuanced view in which cellular signaling pathways intersect with the mitochondria, creating a two-way network of interactions between the consumer (the cell) and the supplier (the mitochondria) of energy(ref).” Instead of just focusing on the health of the inner operations of the cell or the mitochondria, perhaps we need to look more at what they are saying to each other.

So what does the mTOR story contribute to the longevity picture beyond what I have discussed before?  I see it as yet-another interesting area of the longevity puzzle still to be well-integrated with the other ones.

The most recent posts related to progeria diseases remind me again that when it comes to aging we seem to be dealing with different areas of a very large jigsaw puzzle where most of the pieces between the areas are still missing.  The best we can do is assemble different portions of the puzzle without worrying too much about how the portions will eventually fit together.   As we build those portions we find they have irregular shapes with holes in them where smaller collections of pieces are still missing.  We may have put together a portion of the puzzle and not know what it means – is the blue area sky, water or the side of a building?  Is the accumulation of progerin in cells with aging just another irrelevant buildup of a substance in cells with aging, a major cause of other aging effects, or what?  As we proceed we constantly keep looking for how one portion of the puzzle might be joined with another.  Being able to join up two major portions is a breakthrough event.  As time progresses a more and more coherent pattern emerges and the job gets easier.  If you have ever worked on a very large jigsaw puzzle you know what I mean.  

There are differences between the two kinds of puzzles, however.  You know what an assembled jigsaw puzzle looks like because the image is printed on the top of the box.  This image gives important color clues for putting the puzzle together.  And you know you the box should contain exactly the pieces you will need.  You know the pieces are accurately cut.  It might take a week off-and-on to finish a 3000 piece jigsaw puzzle but the job is finite. 

For the longevity puzzle we don’t know what the puzzle will look like when it is finished.  We have to be constantly fishing around in the world literature to find new pieces.  And some of the new pieces we find may be inaccurately shaped even if at first they seem to fit with some other pieces.  What works in a mouse study may not apply to humans.  If we put together a part of the puzzle with inaccurately shaped pieces that part won’t fit in with the rest of the puzzle and will eventually have to be taken apart and built over.  At any point, we don’t know how many pieces are still missing, and we don’t know whether we will live long enough to find them all. So, the longevity puzzle is open-ended and might take 5 years or a lifetime before the picture is reasonably clear.  What fun!