Combining Biochemical Pathways to Longevity: Toward a Recipe for the Youth Pill

From studies in rodents, we now know dozens of treatments that extend life span modestly.  If we could combine their effects all together, we would have a basis for dramatic life extension!  But some of these have biochemical actions that overlap, while others are likely to be independent, and – if we are lucky – some will be synergistic, so that the combined benefit might be greater than the sum of the treatments individually.  Experiments with combinations of longevity drugs are the next big thing in anti-aging research.

 

Deprenyl is an antidepressant and Parkinson’s treatment (sold as Selegeline, Emsam and Eldepryl).  Dinh lang is the Vietnamese name for an Asian plant (Policias fruticosum, not available to my knowledge in the US),  root of which is a traditional medicine.  In 1990, T T Yen and Joseph Knoll worked together on a study of life extension in mice.  Mice treated with deprenyl lived 22% longer; with the dinh lang, there was 28% life extension; and with the two together, an impressive 35% life extension.

Interpretation:  Life extension from the two together is greater than each of the two treatments separately, but not as large as the sum of the two effects.  Whatever dinh lang and deprenyl do for the mouse’s physiology, there is some overlap in their effects, and some independendent action as well.

This twenty-year-old longevity study is the only one I’ve seen in which two treatments are combined to determine how the treatments work in tandem.  A lot more of this kind of work could be done.  Granted, mouse studies are expensive (in the neighborhood of a million dollars for a mouse lifetime, including controls).  But these studies of combined treatments will provide a vital bridge between theory and practical life extension in humans.

We now have evidence for life extension in mammals from many different treatments.  If we could add these effects together, we would have some stunning results!  But it is likely that some of them do essentially the same thing, acting through the same biochemical pathways with different agents.  Only some of the treatments are independent.

What we know about aging suggests that several independent processes are involved; so Practical life extension for humans will involve a combination of different measures. Experiments with combined treatments have the potential to tell us how these pathways may be interrelated, as well as providing practical guidelines for formulating the coming Youth Pill.

The best-known path to life extension works via calorie deprivation or hunger, or simulated hunger.  Calorie Restriction is a probable confounder in many lab studies of life span.  Last year, Stephen Spindler reviewed the literature on life extension studies in rodents, and found that many researchers had not made a clean separation between CR and the particular intervention they were studying.  The problem is that eating less has a strong and reliable benefit for life span, so any drug or herb that tends to suppress appetite may show a positive benefit for life span – a real but secondary effect.  Spindler complains that of the researchers doing life extension studies on mice and rats, very few of them report weight or food consumption, so it is impossible to know if the treatment they are studying has an independent benefit, or if it just induces the animals to eat less.

 

Spindler and Anisimov

The (UC Riverside) laboratory of Stephen Spindler has conducted mouse studies of longevity, reporting largely negative results.  But when Spindler assembled the review (cited above), his criterion was to include every substance that has been reported in a peer-reviewed publication to induce life extension in rodents.  These studies come from differently labs, and the quality is uneven.  Some are corroborated by more than one study from more than one lab, some have never been replicated, and some have been the subject of negative findings in Spindler’s own lab, but he lists them anyway.  Across the ocean, the Russian researcher who is Spindler’s opposite number is Vladimir Anisimov of the Petrov Institute in St Petersburg.  For decades, Anisimov has operated the largest laboratory in Russia devoted to aging medicine, and has reported many positive results, some of which have been replicated elsewhere.  Least known of Anisimov’s findings are the very promising results he has reported with short peptide chains.

I think of Spindler and Anisimov as bookends of the anti-aging literature.  Spindler’s criteria for inclusion are the strictest, and Anisimov’s the most liberal.

 

Categorizing the anti-aging molecules

Dozens of treatments that are reported to extend life span in rodents individually have never been tried in combination, and there are hundreds of potential combinations.  In order to make an educated guess as to which combinations are likely to work better together, it is helpful to categorize their modes of action, as far as they are known.  To this end, I have listed Spindler’s catalog, plus a few more, in nine groups according to their biochemical pathways.  There is considerable overlap in the mechanisms of action, so my criteria are somewhat subjective.  And I don’t claim that this list is exhaustive – it is Spindler’s list, supplemented by other interventions that I happen to know about.  Here are the nine groups, with treatments in each category listed in parentheses underneath:

• CR mimetics / insulin  / IGF
  (metformin, MCP, dinitrophenol, resveratrol, pycnogenol)
• Anti-inflammatory
  (aspirin, NDGA)
• Neuroprotection  
  (ginkgo, deprenyl)
• Mitochondria / ROS  
  (SkQ, CoQ10)
• Anticancer
  (green tea, melatonin)
• TOR = Target of Rapamycin  
  (rapamycin)
• Increased autophagy  
  (spermidine)
• Miscellaneous or unknown mechanisms
  (PBN, dinh lang, short peptides)

Metformin:  I wrote a full column on metformin last year.  It is available only by prescription, but it is out-of-patent and quite cheap.  There is robust evicence for anti-cancer and longevity benefits in diabetics, and I suspect that there are also benefits for non-diabetics, because we don’t yet have data on large numbers of non-diabetic people who have taken metformin.  Several studies find life extension in rodents from metformin [1, 2, 3] and some studies found no life extension.

MCP:  Marine Collagen Peptides  are derived from fish skins, and in one study demonstrated life extension and cancer suppression in mice.

DNP:  Dinitrophenol was found to extend life span modestly in one Brazilian study.  The authors claim the mechanism of action is as a CR mimetic.

Resveratrol is derived from red wine.  After attracting great excitement about ten years ago because of dramatic life extension in tests with yeast cells, flies, worms and fish, resveratrol was first studied in mice in 2007, with much more limited success.  All mice seemed healthier with resveratrol, but life span extension could only be demonstrated for mice on a diet that made them obese.

Pycnogenol is a proprietary extract of French maritime pine bark. It is reported to increase insulin sensitivity in diabetics.  One study showed modest life extension in non-diabetic mice that were genetically short-lived.

Aspirin, ibuprofen, other NSAIDs
Inflammation is associated with all the diseases of old age.  Anti-inflammation is once of the most promising avenues to life extension.  But tests with life span in rodents have shown mixed result.  Here is one positive report for both aspirin and NDGA from a well-respected and conservative research group at Jackson Labs in Bar Harbor.  (NDGA stands for nordihydroguaiaretic acid, a powerful antioxidant and anti-inflammatory derived from creosote.  NDGA is not sold as a human dietary supplement because of concerns about chronic toxicity from chronic use.)

Don’t forget fish oil and curcumin, potent anti-inflammatories from natural dietary sources.  But the only experiment testing for life extension (that I have been able to find) reported negative results.

Deprenyl

Dopamine is a neurotransmitter that decreases with age.  Low dopamine levels in the brain are the proximate cause of Parkinson’s disease, and in this sense, we are all pre-Parkinson’s patients as we age.  Deprenyl is an MAO-B inhibitor, which means that, via indirect action, it inhibits the uptake and disposal of dopamine.  Deprenyl makes dopamine hang around longer.

Another side of deprenyl is its action as a stimulant; it is a chemical cousin of methamphetamine, and it is metabolized to methamphetamine in part.  It can make you manic.

Since the pioneering studies of Joseph Knoll in the 1980s and 90s, there have been several replications, confirming life extension from deprenyl, but quantitatively smaller than Knoll had reported.  Perhaps we should not be surprised.  Science is done by human beings who are interested in the results, and their hopes and dreams find their way into the reported outcomes.  That’s why pharmaceutical companies should not be testing their own products for safety and efficacy, but don’t get me started…

Ginkgo biloba is a common tree from the orient, and its leaves have been used for thousands of years in Chinese medicine.  It has been found to improve cognitive function in animals and in humans.  In one study conducted at SUNY 15 years ago, it was associated with impressive life extension in rats.

Melatonin is a hormone secreted by our pineal glands, and it helps regulate sleep cycles.  We have less of it as we age.  Many studies have been done testing melatonin for life extension and other benefits in rodents.  Results are widely inconsistent.  Anisimov wrote the major review on the subject, and Spindler did not attempt an independent evaluation in his review.

 Green Tea extract

Many authors have claimed health benefits from green tea, and one Japanese study founda small benefit for life extension in mice.

Rapamycin is a powerful immune suppressant, prescribed for organ transplants, and probably not suitable for chronic human use.  Nevertheless, it has illuminated a whole new genetic pathway (TOR=”target of rapamycin”) and it has produced large benefits for life extension in mice, even when administered late in life.

Spermidine

Autophagy is the name of the cell’s main clean-up process, eliminating accumulated wastes.  Spermidine promotes autophagy, and is found in many foods.  As an anti-aging agent, it has been championed by Frank Madeo of University of Graz. He reports dramatic life extension in worms and flies, and smaller life increases in life span for rodents.

CoQ10 and SkQ
Coenzyme Q10, also called ubiquinone, plays a vital role in the body’s energy metabolism, which takes place in the mitochondria.  As we get older, we have fewer mitochondria, less CoQ10, and literally less capacity to turn sugar into energy.  CoQ10 supplement has benefits for heart health, and was considered a promising candidate for life extension.  But most experiments with rodents have not produced positive results. Here is one that has.

Vladimir Skulachev has devoted the latter part of his career to a molecule of his own invention, which combines a chelated, positively charged ion at one end of a carbon chain with a CoQ10 molecule at the other.  The positive ion acts like a tugboat, pulling the molecule through the mitochondrial membrane into the mitochondrion itself, where the CoQ10 can do the most good.  Skulachev’s molecule, nicknamed SkQ, concentrates itself a million-fold inside the mitochondria, where it is needed most.  In experiments with life span and health span, the SkQ molecule (administered eye drops) has reversed cataracts and macular degeneration, and (administered orally) has has extended life span in mice.

So far SkQ is only avaiable as eye drops, and can be purchased only in Western Russia.  Licensing is proceeding in Europe over the next few years, but in America it could easily be a decade away.

I know Skulachev and have great admiration and trust for him, but he has both an academic and a commercial interest in the success of SkQ.  I wish there were someone else working to corroborate his results.

 

Anisimov’s Short Peptide Experiments
A peptide chain is the same as a protein molecule.  All the body’s hormones and enzymes and most of its workhorse molecules are peptide chains, constructed of hundreds or thousands of amino acid molecules, linked together in a precise or, as dictated by the information in DNA. Anisimov’s magic bullets consist of just two or three or four amino acids linked together in a “short peptide chain”.

The Anisimov lab has been experimenting with these substances for decades, and he recently wrote a summary of findings.  Some of the peptide sequences were derived by extracting small molecules from the thymus and pineal glands, both organs that atrophy with age.  Anisimov documented life extension in rodent studies, up to 30%.  He also tested his short peptides on elderly human subjects – an experiment that probably could not have been done in the US – and found mortality rates suppressed by almost half (see table).

How can it be that there are major effects on life span from such small, simple molecules?  Anisimov theorizes that these peptides bind to DNA and act like transcription factors.  In other words, they are regulatory signals, triggering entire cascades of metabolic events.

This is promising work, crying out to be replicated at another lab.

PBN stands for N-tert-butyl-alpha-phenylnitrone, a “spin trap” antioxidant which is thought to act as a source of the signaling molecule NO (nitric oxide) in the body.  In 1998, a group at NIH in Washington, DC found substantial life extension from PBN in the drinking water of a short-lived mouse strain in their drinking water, yet no one has tried to repeat the experiment in 15 years.

Don’t forget telomeres
There are now many herbal extracts that are known to promote expression of telomerase, and (probably) work in vitro to increase telomere length.  Extracts of astragalus, milk thistle, horny goat weed, ashwagandha, tumeric root and fish oil have all shown promise in lab studies.  These substances are unlikely to extend life span in lab mice because, unlike humans, mice already express telomerase copiously through their lifetimes, and mouse telomeres are much longer than human telomeres.  But there are some rodents that don’t express telomerase, and they would make appropriate models for testing telomerase extenders alongside the above medications in life span studies.

 

Exercise, too

Exercise extends average life span in rodents as well as humans, and it should be included in combination tests with other treatments, because exercise and medications can interact constructively or destructively.  Exercise signals the body for life extension with peroxide, which looks a lot like oxidative damage.  There is a stunningly counter-intuitive finding from recent years that anti-oxidants can interfere with the life extension benefits of exercise.

A Social Perspective on Research

The time has come to test combinations, “Chinese menu style” – one from group A and one from group B.  We can look for combinations that do significantly better than either separately.  And as we close in on delaying the all most important pathways of aging, we should, theoretically, find synergy – that the life extension from all our interventions is greater than the sum of the individual benefits.

The million-dollar price tag for a rodent study has been a significant deterrent in the context of paltry and inconsistent support for research in anti-aging medicine.  But for individuals facing death from cancer, insurance companies are paying a million and more just to buy a few months or a year of tortured, debilitated life for a single individual.  A comparable investment in rodent studies will likely yield treatments that add years of healthy life for millions of individuals.  As a society, what are our priorities?  Where is our rationality?  The domination of American medicine by a capitalist model has produced grotesque distortions of medical economics.  The cost in dollars and human suffering are beyond comparison.

There is no longer any doubt that investment in the science of longevity will be vastly more effective than anything else we can do with our budget for medical care.