Chinese Longevity Herb

Fo-ti is a root herb from traditional Chinese medicine that has been used for centuries as an anti-aging tonic, and has shown promise in limited Western-style analyses.  Interest has been held back by reports of liver toxicity, but there is some indication that the benefits can be separated from the toxic effects. In my readings, I found anecdotal evidence for rejuvenation plus one older study of impressive life extension in quails. I also found many more recent studies documenting beneficial biochemical effects which may be counted indirect evidence that makes life extension more credible.  There were two clinical trials, both with promising results.

I’ve been looking into the effects of a root herb called Fo-ti or He shou wu (何首乌) or Polygonum multiflorum Thunbergia, since a friend emailed me about rejuvenating effects when he fed it to his ancient German shepherd.  I’ll call it PMT for the remainder of this page. I’ve consulted the usual PubMed sources, in addition to books on Traditional Chinese Medicine (TCM), and some scientific articles in Chinese, which I ran through Google Translate, with fair results.  

TCM is based on herbal combinations and formulas.  Each ingredient has many active compounds, and the art of TCM is to combine the combinations.  Western medicine likes to study one compound at a time, based on a scientific tradition (reductionism) that tries to understand each separate piece, then study interactions from that understanding as a foundation.  The reductionist approach was responsible for the explosive success of 19th Century physics, and has been popular ever since, but it is not obviously the best way to make progress in 21st Century biology [Carl Woese philosophy piece].  Another reason for the Western preference for single-compound treatments comes from patent law, which encourages the testing of purified compounds and disallows patents for whole plants. But our bodies are complex, homeostatic systems, and it is rarely true that the combined effect of two drugs is just the sum of the effects of each separately.  Strong interactions are the rule, rather than the exception. I believe that we are not going to find a single Fountain of Youth molecule, so I have been an advocate for high-throughput screening of many combinations of treatments, looking for combinations that stand out as especially effective. If we continue to study purified molecules in isolation, it may be a long time before we get to the point where we understand the biochemistry well enough to identify magic combinations on theoretical grounds.

A curious side-note: It is reasonable to expect some combinations of biochemicals to synergize in the human body.  But why should we expect these combinations to be found regularly in a single plant?  Herbal medicines are unreasonably effective in this regard.

Here [1988] is the one lifespan trial that I was able to find, which reports 50% life extension in Japanese quails.  I looked on Cochrane and, and found nothing. However, Joe Cohen over at Self-Hacked has an extensive article. “More than 100 chemical compounds have been isolated from Fo-ti, and the most biologically relevant components have been determined to be from the families of stilbenes, quinones, flavonoids, and phospholipids…Fo-ti exhibits a wide spectrum of pharmacological effects, including anti-aging, immunologic, neuroprotective, anticancer and anti-inflammatory effects.”  Stilbenes are molecules in the resveratrol family; quinones are like CoQ10, and flavonoids are polycyclic molecules in the quercetin family.

Most of the rest of what I report here comes from this Chinese review [王伽伯, 2016] and this English language review [Bounda & Feng, 2015].

Laboratory studies and clinical practice have demonstrated that PMT possesses various biological and therapeutic actions, including anti-tumor,[16,17] antibacterial,[18] anti-inflammatory,[13] anti-oxidant,[19,20,21] anti-HIV,[22] liver protection,[23,24] nephroprotection,[25] antidiabetic,[15,26] anti-alopecia,[27,28] and anti-atherosclerotic activities.[29,30] It has been also reported to exert preventive activity against neurodegenerative diseases,[31,32,33,34,35] cardiovascular diseases and to reduce hyperlipidemia as well.[36,37] — Bounda & Feng

Anti-inflammatory: [13] is a Korean study that found inhibition of inflammatory cytokines in white blood cells of mice.  Other studies [77] show suppression of NFκB.

Liver protection: [23] A Taiwanese study that demonstrated reduced toxicity from CCl4 after mice were treated with PMT extract.  [24] PMT reversed liver cirrhosis in mice.

Antidiabetic: [15] inhibits enzymes that digest starch [26] is an impressive study, that demonstrates inhibition of TGF-β1 and COX-2, and simultaneous enhancement of SOD and glutathione from a chemical extract of PMT called 2,3,5,4′-tetrahydroxystilbene-2-O-β-d-glucoside (TSG).  TSG is chemically similar to resveratrol, and in a worm study was more effective than resveratrol at increasing lifespan (22%).

Anti-atherosclerotic: [29] Mice don’t get heart disease so they work with rabbits.  Large reductions in measures of arterial blockage in rabbits fed a water-extract of PMT.  [30] This is really about anti-inflammatory benefits of TSG fed to mice and rats.

Neurodegeneration: [31] This was about adaptogenic benefit in mice.  Mice were protected from nerve damage by paraquat if they had been prepared with extract of PMT.  [32] worked with a mice that had been genetically modified to give them Alzheimer’s disease.  TSG was found to ameliorate the loss of memory. [33] Older rats lose their memory, as tested in their ability to remember from day to day the location of a hidden platform in a tank of water.  TSG protected memory in older rats. [34] This is a study for people who believe in the Amyloid-β theory of Alzheimer’s disease.  A large number of herbal substances were screened in cell lines that generate Amyloid-β, and the only effective inhibitor was found to be PMT extract. [9] Suppresses lipid peroxidation in response to Amyloid-β in a mouse model and increases glutathione. [116] Another successful trial, this time of TSG in a mouse model of AD. [119, 120 is in Chinese] Two clinical studies found substantial improvement in cognitive performance of AD patients with PMT.

Liver injury from PMT is linked to a certain genetic difference, labeled CYP1A2 * 1C.  I didn’t find anything more about this genetic variant. Curiously, I found several studies that claimed that PMT protects the liver, for example this.

My inclination is to look for empirical evidence and downplay theory (both Western and Chinese theory).  I believe that the emphasis on single compounds is a serious limitation of Western medical research, because the interactions are more important than the individual effects.  For me, it is an attractive feature of TCM that there is so much accumulated wisdom, not just about herbs that contain many active ingredients, but about potions that combine typically a dozen or so herbs that have been found to work well together.  So the maddening thing I’ve found is that the Chinese scientists who have studied PMT and other promising Chinese herbs fall into the Western trap and isolate one compound at a time to study their effects. What is missing is the lifespan studies based on whole herbs, or combinations of herbs, as they would be prescribed by a traditional Chinese herbalist.

I went to a local herbalist this week and asked for advice about He Shou Wu.  She explained to me that in TCM, herbs are always given in combinations. There are classic formulas with 6 or 10 or 20 herbs, and these are adjusted for individual prescription.  The main ingredients are large quantities of the herbs that move the metabolism in some direction, and the lesser ingredients counterbalance the main ingredients by pushing in the opposite direction.  Some of the directions they talk about correspond to observables we might recognize (high or low energy, sexual stimulant), and some of them are more esoteric (wet or dry, hot or cold, yin or yang). She gave me a formula with He Shou Wu as the main ingredient, and I’m going to do some more reading before I decide whether to take it.

In the meantime, I’m taking a gram of He Shou Wu extract processed with black beans each morning before breakfast and I think I detect an increase in aerobic stamina which has not listed anywhere as one of the benefits.

Acknowledgement: The idea for this research came from Jeff Bowles, who is a frequent commenter on this blog.  The Chinese research was kindly supplied by Wen-jun Li, a post-doc in the Beijing lab where I have worked the last 3 summers.

If you’re over 50, don’t stop taking aspirin

This week, a headline-making study in the New England Journal of Medicine sought to cast doubts on long-established science that says daily aspirin can be a broadly-effective anti-aging tonic.  I’m writing this response because I think that this new, small study has to be viewed in the context of many larger studies over many decades that together make a solid case for aspirin’s benefits.  

Aspirin has two kinds of effects: First, aspirin thins the blood, reduce clotting, which lowers the risk of most kinds of heart attacks and stroke (ischemic) while raising the risk of bleeding ulcers and  hemorrhagic stroke.  Second, aspirin lowers the level of systemic inflammation, which reduces risk of heart disease, stroke, most cancers, and Alzheimer’s disease.

Historically, daily low-dose aspirin began to be prescribed broadly to middle-aged and older adults in the 1960s as the medical establishment theorized about the first effect.  This led to a grand natural experiment—tens of millions of older people taking low-dose aspirin. Studies comparing these people with matched populations who didn’t take aspirin have shown lower rates of all-cause mortality, Alzheimer’s dementia, and of cancer and probably of heart disease as well.  These studies are based on millions of tabulated deaths. The current study is based on 1052 total deaths in the aspirin group and the placebo group, and the difference between the two was barely statistically significant in the direction against aspirin.

Summary of past studies

Eidelman, JAMA, 2003: Summarizing 5 trials, they found aspirin was associated with a 32% reduction in the incidence of first heart attacks.  Statistical significance was 2 chances in 100,000 (p<0.00002).

Methods  A computerized search of the English literature from 1988 to the present revealed 5 published trials: the Physicians’ Health Study (22,071 participants), the British Doctors’ Trial (5,139), the Thrombosis Prevention Trial (5,085), the Hypertension Optimal Treatment Study (18,790), and the Primary Prevention Project (4,495).

Results  Among the 55,580 randomized participants (11,466 women), aspirin was associated with a statistically significant 32% reduction in the risk of a first MI and a significant 15% reduction in the risk of all important vascular events, but had no significant effects on nonfatal stroke or vascular death.

Conclusions  The current totality of evidence provides strong support for the initial finding from the Physicians’ Health Study that aspirin reduces the risk of a first MI. For apparently healthy individuals whose 10-year risk of a first coronary event is 10% or greater, according to the US Preventive Services Task Force and the American Heart Association, the benefits of long-term aspirin therapy are likely to outweigh any risks.

Rothwell, The Lancet 2011: Summarizing 8 trials, they found aspirin was associated with a 21% reduction in the incidence of all cancers.  Statistical significance was 1 chances in 10,000 (p<0.0001).

In eight eligible trials (25,570 patients, 674 cancer deaths), allocation to aspirin reduced death due to cancer (pooled odds ratio [OR] 0·79, 95% CI 0·68–0·92, p=0·003). On analysis of individual patient data, which were available from seven trials (23,535 patients, 657 cancer deaths), benefit was apparent only after 5 years’ follow-up (all cancers, hazard ratio [HR] 0·66, 0·50–0·87; gastrointestinal cancers, 0·46, 0·27–0·77; both p=0·003). The 20-year risk of cancer death (1634 deaths in 12 659 patients in three trials) remained lower in the aspirin groups than in the control groups (all solid cancers, HR 0·80, 0·72–0·88, p<0·0001; gastrointestinal cancers, 0·65, 0·54–0·78, p<0·0001), and benefit increased (interaction p=0·01) with scheduled duration of trial treatment (≥7·5 years: all solid cancers, 0·69, 0·54–0·88, p=0·003; gastrointestinal cancers, 0·41, 0·26–0·66, p=0·0001). The latent period before an effect on deaths was about 5 years for oesophageal, pancreatic, brain, and lung cancer, but was more delayed for stomach, colorectal, and prostate cancer. For lung and oesophageal cancer, benefit was confined to adenocarcinomas, and the overall effect on 20-year risk of cancer death was greatest for adenocarcinomas (HR 0·66, 0·56–0·77, p<0·0001). Benefit was unrelated to aspirin dose (75 mg upwards), sex, or smoking, but increased with age—the absolute reduction in 20-year risk of cancer death reaching 7·08% (2·42–11·74) at age 65 years and older.

Wang, Journal of Alzheimer’s 2015: Summarizing 11 trials, they found aspirin was associated with a 49% reduction in the incidence of dementia.  Statistical significance was less than 1 chances in a billion (p<0.0000000005).

Objective: Alzheimer’s disease, the most prevalent dementia, is a prominent source of chronic illness in the elderly. Laboratory evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) might prevent the onset of Alzheimer’s disease. Since the early 1990s, numerous observational epidemiological studies have also investigated this possibility. The purpose of this meta-analysis is to summarize and evaluate available evidence regarding exposure to nonaspirin NSAIDs and risk of Alzheimer’s disease using meta-analyses of published studies. Methods: A systematic search was conducted using Medline, Biological Abstracts, and the Cochrane Library for publications from 1960 onwards. All cross-sectional, retrospective, or prospective observational studies of Alzheimer’s disease in relation to NSAID exposure were included in the analysis. At least 2 of 4 independent reviewers characterized each study by source of data and design, including method of classifying exposure and outcome, and evaluated the studies for eligibility. Discrepancies were resolved by consensus of all 4 reviewers. Results: Of 38 publications, 11 met the qualitative criteria for inclusion in the meta-analysis. For the 3 case-control and 4 cross-sectional studies, the combined risk estimate for development of Alzheimer’s disease was 0.51 (95% CI = 0.40–0.66) for NSAID exposure. In the prospective studies, the estimate was 0.74 (95% CI = 0.62–0.89) for the 4 studies reporting lifetime NSAID exposure and it was 0.42 (95% CI = 0.26–0.66) for the 3 studies reporting a duration of use of 2 or more years. Conclusions: Based on analysis of prospective and nonprospective studies, NSAID exposure was associated with decreased risk of Alzheimer’s disease. An issue that requires further exploration in future trials or observational studies is the temporal relationship between NSAID exposure and protection against Alzheimer’s disease.


Problems with the present study

Because of small numbers and short duration, the result of the study was only marginally significant (p<0.05).  The aspirin group had higher cancer rates and lower heart attack rates than placebo.

Typically, doctors advise patients to start low-dose aspirin around age 50, but this study was with patients more than 70 years old who had no cardiovascular symptoms by age 70.  Most people by age 70 have had some cardiovascular diagnosis before age 70, so this is an unrepresentative sample. The study fails to address the question, how many deaths and how many diseases could be avoided between the ages of 50 and 70?  This is the period in life when inflammation is most active, and a great deal of destruction of the body’s veins, joints, and nervous system happens during these years. Excluding those with a history of heart disease during those ages is excluding just the people most likely to be helped by aspirin.  Of course, when you’re 50 and considering whether to start on aspirin, you may not know whether you’re lucky enough (or have the right genes) to be in the group that will do fine for the next 20 years without it.

This table breaks the composite test group into sub-groups according to various criteria.  Dots to the right of the line mean “aspirin was worse”, and to the left mean “aspirin was better”.  Among the subgroup in the US, aspirin was better. Among people who had never taken aspirin before, aspirin was better.  Among people within fairly wide limits of a “normal” weight range, aspirin was better.

Why are we seeing this?

Scientists are only human, and their environment, their preconceptions, and their incentives shape the way that statistics are handled.  In my experience, it is not difficult to make a small effect look like a (p<0.05) effect by making consistent choices in the way the data are treated, none of which are suspect or dishonest.  If the group had come up with the conventional and accepted conclusion based on such a small study, there would have been no prominent publication, no headlines, probably no follow-on grant. So they had every incentive to perform the analysis in a way that makes the results appear more interesting than they are.