Life Extension Methuselahs

How to increase your chances to become one of the …

Compiling research indicates that you might live a lot longer 
with protein refolding supplements, such as trehalose
 
Stephen Coles, M.D., PhD., is the Executive Director of the Gerontology Research Group (GRG), an association that concentrates its research on long-lived people and especially supercentenarians (individuals living more than 110 years). Currently, there are 68 validated worldwide living supercentenarians: 67 women and 1 man. Dr. Coles has written about the Group’s research and has recently reported on a rather remarkable finding with great importance for radical life extension.1

Amyloidosis Identified as Killer of Super-Aged

In this report,1 Dr. Coles and coauthor Dr. Robert Young have identified what is killing those who have achieved great longevity: the accumulation of a damaged protein called Transthyretin (TTR), which results from misfolding aggregations that build up in blood vessels. The disease that causes this is called Transthyretin Amyloidosis (TTRA), an autosomal dominant (hereditary) degenerative disease, which arises and wreaks havoc with longevity when the TTR gene is mutated and interferes sideswipes cardiovascular health, as we shall see. At the same time TTRA disease severely impacts the transport of the important thyroid hormone, thyroxin, throughout the body (see sidebar, “The Importance of Thyroid”).

The Importance of Thyroid

The Transthyretin (TTR) protein, produced principally in the liver, is a carrier for thyroid hormones and Retinol Binding Proteins. Retinol is a form of vitamin A. There are two other thyroid-transport proteins in addition to TTR, Thyroid Binding Globulin (TBG) and Albumin, making for three in all. While TBG has the highest affinity for thyroxin (T4), it is low in concentration; leaving most of the thyroid-transport work to be done by TTR and Albumin, which are higher and much higher, respectively, in concentration. This redundancy of these three delivery vehicles suggests that thyroxin (T4) is extremely important in the body to maintain basal metabolic rate and body temperature within tight limits.


A recent study reports on the results 
of supercentenarian autopsies, which 
are of great importance for radical 
life extension.

The Failure to Preserve Proper Folding Function

Proteins have complex three-dimensional structures that that are instrumental to proper functioning and stability. Consequently, the quality control for protein folding is very important to health and longevity. When misfolded proteins are produced from the degeneration of TTR, the damaged proteins aggregate into long fibers that amass on the interior surface of our blood vessels and throughout our tissues. The TTR protein—a carefully folded 127-amino-acid polypeptide chain, rich in beta-pleated-sheet structures—normally acts to transport thyroid hormone and retinol (this is how the nomenclature for Transthyretin is derived). But when TTR is damaged by not refolding properly, it forms sticky amyloid fibers, which accumulate and block normal organ function. This can damage the peripheral nerves and the heart and can result in intractable peripheral sensory neuropathy, autonomic neuropathy, and cardiomyopathy. In the earlier years of life, cardiomyopathy is non-fatal. However, with greater age, it can result in a cause-of-death diagnosis as Congestive Heart Failure (CHF), and possibly in earlier ages as well.

The Desire of Longevists

The Coles and Young paper likens this to the APO-E mutation that increases the probability of “Alzheimer’s disease as a cause of death, unless, of course, one were to escape from all other forms of death, so that this particular form might then reveal itself.” The researchers project a time, not far in the future, when costs continue to drop dramatically for full genome sequences, so that they become commonplace. Then, as hundreds of thousands of such sequences are available to search, scientists will be able to associate CHF death certificates with a variety of TTR mutations and thus see the causal connections more clearly. The need to take preventive actions will be more demonstrable, which is the type of information longevists (those desiring to live a long time) crave.

Researchers have identified what is 
killing those who have achieved 
great longevity: the accumulation of 
a damaged protein 
called Transthyretin, which results 
from misfolding aggregations that 
build up in blood vessels.

Amyloidosis More Common than Thought

While the TTR type of Amyloidosis has been known about since the 1950s, it now appears to be less the result of heredity and more the result of degeneration than previously thought. Writing about the commonality of amyloidosis, two estimable amyloid researchers2 noted that “in the 1920s, [amyloidosis] was then considered an extremely rare degenerative condition,” but now “it has become apparent, however, that amyloidosis is far more common than had been thought, that it is often of great significance, and that it is associated with an extraordinarily wide variety of diseases.”

The FDA will never approve a life 
extension drug.

Transthyretin Amyloidosis: Primary Cause of Death in the Super Aged

In fact, in Drs. Coles’ and Young’s report, TTRA was determined to be the primary cause of death for 70% of supercentenarians who have been autopsied by Dr. Coles (the balance of deaths were due to aspiration pneumonia). Supercentenarians have already avoided most other typical causes of death such as cardiovascular disease, cancer, diabetes, and so on. But with the great length of their lives, what was not a problem in earlier years—harmless amounts of TTRA—grows larger with each passing year, and at a certain point become deadly.

Is Amyloidosis the Limiting Factor for Humans Lifespan?

While the number of supercentenarian autopsies conducted is not sufficient to have great statistical power, the study certainly provides support for the hypothesis that TTRA could also be a health tipping point for people at other older ages, say from their 60s through their nineties We do know that beta-amyloid plaque (an amyloidosis principally of the brain) becomes a real concern as we age, and becomes directly associated with severe neurodegeneration, such as Alzheimer’s disease with advanced age. The curve for Alzheimer’s turns sharply upward in the 80s. This parallels TTRA, and suggests a a need for preventive measures.

Accumulative research indicates that 
there are nutrient solutions to 
misfolded proteins, including 
Transthyretin Amyloidosis.

Coles and Young believe that it is still too early to draw definitive conclusions (but of course!). Nonetheless, their early results suggest that we need to take a second look at implicating amyloidosis as one of the major components of the aging process. One of the questions that remains for Coles and Young (and for longevists) is whether TTRA is just part of the aging process, and therefore not addressable except as a whole, or whether if it is another chronic disease that is possible to treat?

Drugs to Correct Misfolded Proteins: The Next Frontier?

Drs. Coles and Young recognize that TTRA is a protein-folding problem. From their report, “Any of several different mutations (or SNPs [single-nucleotide polymorphisms]) in the TTR gene may result in misfolded, sticky amyloid proteins that aggregate into long fibers that can accumulate on the interior surface of blood vessels.”1 But is it just the SNPs, or do we need to be concerned with the mechanism repair?

At the end of their paper, the authors seem to be attracted to the drugs that have been used to treat the three recognized TTRA conditions: (1) Senile Systemic Amyloidosis; (2) Familial Amyloid Polyneuropathy; and (3) Familial Amyloid Cardiomyopathy. These drugs include: Diltiazem, Verapamil, Celastrol, 4-PDA, taurine-conjugated ursodeoxycholic acid, and CHPHC, which are under development for the management of the disease. They write, “It seems to us that these questions [about the drug viabilities] may lead us to the next frontier in the extension of human lifespan. At the very least, the recognition that amyloidosis is a common and treatable condition in the oldest old should lead supercentenarians to having a better quality of life in the future, a further confirmation of what has been called the ‘Compression of Morbidity.’”

Yet these drugs all possess assorted side effects, some quite serious, such as hypotension, bradycardia, dizziness (Diltiazem); headaches, facial flushing, dizziness, lightheadedness, swelling, increased urination, fatigue, nausea, ecchymosis, galactorrhea, constipation, and gingival ­hyperplasia (Verapamil); “accompanied by toxic side effects” (Celastrol); and so on.

FDA Will Never Approve a Life Extension Drug

The case can be made that amyloidosis (even TTRA) begins far earlier in life. But even if TRRA can be treated with drugs, will that lead to increases in human lifespans? Other drugs are in development, but if we have to wait on the development of a new drug, the answer would have to be “never.” That’s because the FDA will certainly not approve a life extension drug.

An important class of 
natural chemical chaperones that 
help stabilize the proper folding 
conformation of proteins 
are the osmolytes. 
These include betaine, inositol, 
taurine, glycero­phosphocholine, 
choline, and creatine.

In late 2011, the European Medicines Agency approved the Transthyretin kinetic stabilizer Tafamidis, discovered by Jeffery W. Kelly and developed by FoldRx pharmaceuticals (acquired by Pfizer in 2010) for the treatment of Familial Amyloid Polyneuropathy (FAP) based on clinical trial data. Tafamidis (20 mg, once daily) slowed the progression of FAP over a 36-month period and importantly reversed the weight loss and muscle wasting associated with disease progression. More recently, Japan has approved Tafamidas.

While this drug has a shorter way to go to progress through the final stages deemed necessary by the FDA, it has a lot of side effects, including urinary tract infection (infection of the structures that carry urine), vaginal infection, upper abdominal pain and diarrhea. Not too bad, one might say, but this is NOT something that is about to be used for prevention of TTRA anytime soon, if at all. Once again, the FDA will never approve a life extension drug. Memory Pharmaceuticals Corp. (now owned by Hoffmann-La Roche) was created to offer memory enhancement drugs, but that has degenerated into drugs for neurological diseases!

Not a Strong Advocate of Rational Supplementation

As with many medical researchers, Dr. Coles appears to be familiar with nutritional science, but only somewhat. For example, he advocates small servings of multivitamins (Centrum!), along with others nutrients such as fish oil, and vitamin D, but not anywhere near optimal levels for many of his recommendations.* The shortcomings are compounded by his advice that all supplements should be taken only once per day, independent of their half-lives, some of which are only 4 hours! While a few of his supplement recommendations are better, for which he is to be commended, it is clear that Dr. Coles is not a nutritional scientist.

* See http://www.bridgeplan.org/bridge-plan/.

At the same time, however, Dr. Coles appears to be somewhat of an apologist for the FDA. In a TV interview, he said, “I like the FDA to be risk adverse … the [FDA] slows the rate of innovation to some extent but it also stops crazy things from happening, which take place in the non-pharmaceutical, nutraceutical field where there is no regulation …”3 Does this mean that crazy things don’t happen in the drug industry, like taking 16 years to approve beta-blockers, after they had been approved in Europe, at the cost of up to 90,000 avoidable deaths per year.

Will there be Life Extension Drugs for Reversing Transthyretin Amyloidosis?

If we have to wait on the development of a new drug approved for the elderly to extend their lives, at a time when the government will be rationing medicine, the answer to the above question would probably have to be “never.” To repeat, the FDA will never approve a life extension drug.

If one wants to reach advanced age in 
good condition, maintaining proper 
protein structure is vital.

At best, the belief that the FDA will come to the rescue, in time is a “far-sighted” mistake, because the drugs will never be indicated for the potential beneficiaries and because there is a current solution of the problem.

Misfolding Correction Nutrients

Accumulative research indicates that there are nutrient solutions to misfolded proteins, including TTRA. (See “The Origami of Aging” in the September 2008 issue of Life Enhancement.) The next three paragraphs quote this breakthrough article.

“A variety of age-related diseases, such as neurodegenerative conditions (including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis), are associated with aggregation of proteins due to improper folding. Other conditions (known as “conformational diseases”) associated with improperly folded proteins include cancer, cystic fibrosis, emphysema, liver disease, prion disease (such as mad cow) and even chronic pain (opioid receptors misfolded in the endoplasmic reticulum).4” This quote is from “The Origami of Aging.” Protein aggregation may also cause cataracts.

“Accumulation of protein aggregates and misfolded moieties is a nearly universal phenomenon during aging. Such aggregates have been specifically referred to as amyloids, lysosomal lipofuscin, ceroid bodies, advanced glycation end-products (AGEs), and cytoplasmic inclusions observed in senescent cells, as well as in affected tissues of age-associated diseases such as diabetes and Alzheimer’s disease.”5 “… more general perturbations to protein folding homeostasis, referred to as proteotoxicity, tend to manifest later in life and are closely linked to the time- and use-dependent attrition to cellular and organismal function recognized as aging.”6

Natural Stabilizers of Protein Structure

“An important class of natural chemical chaperones that help stabilize the proper folding conformation of proteins are the osmolytes. These include betaine, inositol, taurine, glycerophosphocholine, choline, and creatine.5 The principal organic osmolytes in the mammalian brain include amino acids (such as proline, alanine, and glycine), choline, creatine, inositol, and taurine.5 The osmolytes are maintained at particularly high concentrations in the kidneys, which are exposed to high osmolality (high concentrations of salt and urea), but cells in other tissues can also be exposed to hyperosmolality, although to a lesser extent than in the kidneys. Plants, bacteria, and yeasts also rely on the same and some other (e.g., trehalose) osmolytes for protein stability. We [Durk Pearson & Sandy Shaw] have been taking a cocktail of osmolytes—including proline, betaine, inositol, taurine, creatine, and glycine—for several months to help maintain our proteins in a properly folded state. We recently added beta-alanine to the mix. [And more recently trehalose.] Although one probably won’t, in the short term, notice anything as a result of improved protein folding, if one wants to reach the longer term in good condition, maintaining proper protein structure is vital.”

The Next Frontier of Human Life Extension

So here you have an abbreviated case for improving protein-refolding and thereby reaching older age in good condition and even perhaps contending for a Methuselah-type lifespan.

 

References

  1. Coles LS, Young RD. Supercentenarians and transthyretin amyloidosis: the next frontier of human life extension. Prev Med. 2012 May;54 Suppl:S9-11.
  2. Cohen AS, Skinner M. Amyloidosis of the Liver. In: Schiff L, Schiff E (Eds.), Diseases of the Liver. Philadelphia, PA: JB Lippincott; 1993:1465.
  3. Balaker T. Reason TV: Who Wants to Live Forever? Dr. Stephen Coles on the Secrets of the World's Oldest People. Mar. 21, 2011. http://reason.com/blog/2011/03/21/reason-tv-who-wants-to-live-fo. ­Accessed: December 19, 2013.
  4. Papp E, Csermely P. Chemical chaperones: mechanisms of action and potential use. Handb Exp Pharmacol. 2006;172:405-16.
  5. Burg MB, Ferraris JD. Intracellular organic osmolytes: function and regulation. J Biol Chem. 2008;283(12):7309-13.
  6. Yun C, Stanhill A, Yang Y, Zhang Y, Haynes CM, Xu CF, Neubert TA, Mor A, Philips MR, Ron D. Proteasomal adaptation to environmental stress links resistance to proteotoxicity with longevity in Caenorhabditis elegans. Proc Natl Acad Sci USA. 2008;105(19):7094-9.