[Image Source: Steffen Boelaars]
A few weeks ago I learned about a crowd-funded project on the topic of longevity. Maria Konovalenko is a Ph.D. student of Biology of Aging from the University of Southern California and the Buck Institute for Research on Aging. She and her team want to create a comprehensive book, Longevity Cookbook, that will help people live as long and as healthy as possible. The project was successfully funded on June 16, 2015. They raised $57,770.
The table of contents of this book lists chapter titles like: ‘Longevity genetic engineering’, ‘Aging, inflammation, immune response’, ‘Personalized nutrition’, ‘Geroprotectors’, ‘Microbiome’, and many other catchy headlines.
In March 2016, the team has published the first chapter of the book for free online. It’s a long read on the pharmacological means we could currently use for the purpose of prolonging healthy life-span (healthspan). It basically discusses pro-longevity compounds. In the next few lines I’ll provide the short, more comprehensive, version of this list of chemicals.
The List of Compounds
1. Bisphosphonates – preventing the loss of bone mass
In industry, they have been used as water softeners, helping to prevent calcium carbonate precipitation. In living organisms they may inhibit the activity of osteoclasts (cells that break down bone tissue).
2. Rapamycin – targeting mTOR
mTOR (mammalian target of rapamycin) is a nutrient sensing pathway. Nutrient abundance turns mTOR on, leading to growth and cellular division. Nutrient scarcity turns mTOR off, making cells more resistant to stress. Turning down mTOR/TOR increases lifespan in multiple organisms. Protein intake has been shown to influence mTOR.
3. Ubiquinone – increasing redox potential
In mitochondria (the power plants inside your cells), ubiquinone (Q10) acts like an electron acceptor, providing protection from the damage of increased free radical production. There is an issue of poor absorbability with the Q10 you find in most health stores. It fails to get inside the mitochondria. MitoQ and SKQ are two products designed to deal with this problem, allowing Q10 to accumulate inside mitochondria.
4. Metformin – increasing insulin sensitivity
A glucose sensitizer, it acts primarily by reducing gluconeogenesis (production of glucose in the liver). A study published in 1995 followed 3,867 patients for 10 years. It found that metformin reduces the risk of heart attacks and all-cause mortality. Another, more recent, study published in 2014 compared ~78,000 patients on metformin with matched controls. Those on metformin had 15% lower mortality.
More importantly, a study called MILES (Metformin in Longevity Study) has recently received FDA approval and its purpose is to follow the health progress of men and women of 60 years of age or older who will be taking metformin. Since metformin has been shown to be positively associated with longevity in many animal models and in humans, it would be interesting to see the outcomes of this study.
5. Aspirin – inhibits COX1 and COX2 to reduce pain and inflammation
It has been shown to reduce the risk of heart attacks and of developing different forms of cancer. It was also shown to have positive effects on lifespan in mice.
Similarly to aspirin, ibuprofen was shown to reduce the risk of developing Alzheimer’s Disease by 40% and Parkinson’s Disease also by 30-40% . It was positively associated with increased median lifespan in model organisms such as yeast, worms, and fruit-flies.
This is an anti-diabetes medication that lowers post-prandial (after-meal) spike in blood glucose levels. It is well tolerated by most people and it was shown to positively impact lifespan in mice. Its major downside is that it increases flatulence in ~78% of the subjects.
This is a non-feminizing estrogen thought to protect the brain and the mitochondria. It is associated with positive lifespan increase in male but not female mice. This is in accordance with the hypothesis that females already benefit from the protective effects of estrogens.
9. NDGA (Nordihydroguaiaretic acid)
Associated with increased lifespan in mosquitoes, fruit flies, and male mice. Since it is associated with increased liver toxicity in humans, I do not see the relevance of mentioning it.
10. STACs – Sirtuin Activating Compounds
Sirtuins (class of proteins that regulate metabolism) have been associated with extended lifespan in model organisms. Activating sirtuins leads to a situation similar to caloric restriction. Resveratrol (found in red wine) is one of the compounds that activate sirtuins.
I think there’s a lot of controversy and many potential conflicts of interest around sirtuins and STACs, so we have to be very reserved and skeptic when reading studies on this subject.
11. Alagebrium (ALT-711)
Claims were made this compound could reverse age related damage that has already occurred. Its proposed mechanism for increasing lifespan is by breaking down AGE (advanced glycation end products). Studies have found mixed results, which is one of the reasons the company behind it has decided not to develop it further.
“Another way to reduce AGEs is through amino guanidine, which can inhibit AGE formation. Interestingly, this molecule is related to metformin (dimethyl biguanidine) and it is hypothesized that metformin may also have this effect.”
Confers neuroprotection in many animal models by reducing inflammation, increasing neurogenesis and helping angiogenesis. Patients with bipolar disorder that are on lithium have a thicker cortex and more grey matter compared to controls. Another study proposes that lithium slows cognitive decline.
Conversely, animals on a low lithium diet show higher mortality and more reproductive abnormalities. Side effects such as polyuria, hypothyroidism, hyperparathyroidism, and renal failure have been associated with lithium, which is why I’d refrain from getting excited about this for lifespan extension purposes.
Its proposed mechanism is that of inhibiting glycolysis, thus creating a deficit of energy and leading to mitochondrial biogenesis as a result. Often used for joint health, it has been associated with 20% lower mortality in people taking it over the study period. It has been shown to extend lifespan in model organisms such as worms and mice.
14. C60 Fullerenes
60 carbons bound together make up a Buckminsterfullerene (C60). When adding carboxyl groups to C60 it leads to the formation of SOD (superoxide dismutase) mimetics – a very important part of the cellular antioxidant system.
15. Telomerase Activators
Telomeres are like end caps on chromosomes inside the nucleus of every cell in the body. With each cell division, telomeres get shorter. When they become too short, the cell stops dividing. Telomerase is an enzyme to lengthen telomeres’ length. It is expressed differently in different cells.
Some propose that telomere lengthening could increase lifespan. Thus, using telomerase activators would make sense. There is a big debate on this topic since one may not want to indiscriminately increase telomerase activity (think of cancer cells). Studies have been conducted with mixed results. Read the entire chapter for a better insight on this.
It seems difficult to find good data on the subject of aging. Conducting ongoing human longevity studies is most often unfeasible as it may take a very long time to derive insight from them. This is why we mostly rely on analyzing past data from observational and retrospective studies on humans. We also rely on conducting studies in model organisms with shorter lifespan – yeasts, mice, flies, worms, and some primates.
Metabolically speaking, longevity and healthy life-span seems to be associated with:
– decreased activity of mTOR– lower insulin and IGF-1 signaling– increased activity of the AMPk pathway– lower T3 levels (triiodothyronine)– lower growth hormone activity (mixed results)– and a few others.
For that matter, I personally focus on nutrient rich caloric restriction with emphasis on the intake of micronutrients and phytochemicals, on protein restriction, on fasting (intermittently and/or prolonged), on intense exercise (hormesis) as well as using supplements like alpha lipoic acid and resveratrol. Metformin and NMN are some of the compounds that I’d also like to use in the future. Thoughts and comments below.
Image by: Steffen Boelaars. Retrieved from Flickr.
Cristi Vlad holds a Master of Science (M.Sc.) in Civil Engineering. He did not profess in the field yet. He got absorbed into self-experimentation and writing books about the details of his experiments. More, on his personal blog: http://cristivlad.com