We saw in Part 1 that it’s it’s well established that calorie restriction (CR) promotes longevity. We also covered some other mechanisms pertaining to protein restriction that may also play a role. Finally, we talked about the various pathways in which the vegan diet can be conducive to CR and PR, and by extension how following a well-planned vegan diet may promote longevity.
What we’re going to do in Part 2 is cover what are known as calorie restriction mimetics. These are compounds, found exclusively in plant foods, that are thought to activate pathways similar to those activated by calorie restriction.
As you know, I like to distinguish between benefits of a plant-based diet based on what it excludes as well as what it promotes. So, this section is about how a healthy whole food vegan diet may promote longevity based on what it offers in abundance: bioactive compounds, phytochemicals, etc.
What’s so Special About Mimetics?
While it’s established that calorie restriction extends life in a variety of species, who on earth would actually be willing to undergo significant calorie restriction over a lifetime? There is a small community that tries to do just that, but that’s a bridge too far for most people. Not to mention, you can only restrict calories so much before you dip below the bottom end of what’s considered a healthy BMI range—18.5.
I don’t know about you, but I’d much rather eat an abundance of healthy whole plant foods, and a few supplements if they turned out to be effective.
Exactly What Are CR Mimetics?
These chemicals found in abundance in the plant kingdom. They’re often plant pigments, such as anthocyanin—the blue-red pigments found in blueberries, etc.
Why would a simple plant pigment be protective? Many of these compounds protect the plant from:
- UV radiation (by filtering light)
- The ozone
- Extremes in temperature
- Dryness, drought
- Infections (fungal, etc.)
There’s also something called xenohormesis. This is a bit of a tangential note, but it’s so cool and I thought you fellow science nerds would appreciate it.
Many of these plant molecules interact with key regulators of mammalian physiology in ways that benefit health. Some researchers think that plants make special compounds in response to stress and that animals and fungi may be able to use these compounds as chemical cues.
In serving as a chemical cue, these molecules provide advance warning about worsening environmental conditions, so that the animals can go into doomsday prepper mode while conditions are still favorable.
Interestingly, the concentration of polyphenols shown to have life-extending properties in lab experiments is approximately 10 μM—a level similar to the amounts found in fruits and leaves of plants undergoing stress.1-3
Does the connection between longevity and the experiencing of stress sound familiar? These molecules interact with the nervous systems of mammals inducing these positive effects that result in longevity. Moderate calorie restriction is considered a mild stressor which is why these phytonutrients and calorie restriction are thought to trigger the same pathways leading to longevity.36
What’s amazing is that these chemicals, while produced to protect the plant, are not only perfectly safe for humans, but potentially beneficial. This despite having multiple actions within our cells.4
There are numerous different natural bioactive chemicals. These have a vast array of different, and often overlapping, beneficial actions on the body.
And, of course, mimetics include many classes of plant compounds—pigments are just one example.
The majority of phytochemicals covered in this article are what are known as polyphenols: a wide-ranging class of molecules found in plants that are consumed by mammals.
They are characterized by having a large number of phenols. The term phenol is an organic chemistry term for a certain class of compounds. Not really important here.
Remember the strange word xenohormesis from above? It’s thought that a plant’s polyphenol content may make up its chemical signature—the signature indicating environmental conditions.1
How does this work? Howitz and Sinclair believe that these molecules activate certain enzymes in mammalian stress-response pathways, giving it the signal that it may need to migrate or make certain preparations to survive deteriorating conditions.
Though they can be used by plants to deter herbivores, this is not to be confused with the natural toxins that some plants produce to prevent predation. Not to say they can’t be toxic.
Any chemical that’s useful is bioactive, and anything bioactive can be toxic in high enough doses. However, most natural polyphenols have very low toxicity—as in you’d have to administer extremely high levels for the chemicals to show toxic effects.5
So, I mentioned above that polyphenols are a class of phytonutrients that will be covered heavily in this article. There are certain subclasses of polyphenols made naturally by plants which include:
Among the most extensively studied polyphenol subclasses are… well, basically just resveratrol. Quercetin, catechins, and genistein have quite a
If all the types, subtypes, and sub-sub-sub types of polyphenols are confusing, d
A Note on the Exact Function of Polyphenols in Humans
The go-to answer for the protective effects conferred to animals has always been that polyphenols serve as antioxidants. While the antioxidant capacity of these compounds likely plays a role, it’s a bit simplistic to contribute all of the beneficial effects to antioxidant capacity.
The longer answer is that they are involved in various signaling pathways within our cells, which indirectly decreases damage done by ROS—among other things.
Too Good to Be True?
Is it really possible that one pop a few pills, eat a healthy diet and extend life? Is it possible to follow a few protocols and prevent premature death from the most common diseases of aging? What we’ll do in this article go over the latest evidence for such claims.
If you’re thinking that all of this may be too good to be true, then consider that the use of bioactive plant compounds for pharmacological applications is hardly new:1
- Antibiotics—compounds synthesized to prevent fungal infection.
- Aspirin—compounds known as salicylates have a derivative that’s used widely to reduce pain and inflammation. This was actually figured out as early as 1763 when the anti-inflammatory properties of willow bark were first noticed. Imagine what we can figure out with today’s technology.
We could very well be at the edge of a new epoch in the are of using natural compounds for health. There’s no reason to think that antibiotics and the like exhaust the use of plant molecules.
Also, given the fact that we already consume such natural compounds in our diet when we consume fruits and vegetables. And as we saw in Part 1, a diet rich in these food groups has proven to be effective in extending lifespan.
If consuming these compounds ad lib from crude sources confers so many health benefits, there’s no reason to think that, if science figures out which compounds are doing what, we won’t be able to amplify the same benefits by consuming the isolated compounds in pill form.
It’s a good time to note that as of now, it seems that the best action you can take is to consume whole plant foods. There’s very little known about the compounds covered here, and so far nothing in pill form has been able to match the benefits of diets rich in fruits and vegetables, legumes and whole grains.
This article is about what’s on the horizon. Pretty exciting stuff.
Perhaps the most famous polyphenol of all (great now I have Rudolph stuck in my head).
It makes the news a lot, probably because the wine industry loves to talk about it (it’s present most notably in the skin of grapes and other berries).6
Mechanism of Action
Resveratrol regulates the function of a wide array of enzymes and receptors and acts on various transcription factors.7
Many studies have demonstrated a wide range of health benefits from this compound.5
Do you remember NAD+ from biology and biochemistry? Well, there’s a category of enzymes that are NAD+-dependent—that is, they use NAD+ in redox reactions. Specifically, there’s a group of these enzymes known as sirtuins, of which there are seven in mammals: SIRT1 to SIRT7.8
It’s thought that resveratrol acts, at least in part, through activating this group of enzymes, which can accomplish a lot of good stuff.9,10
Specifically, it’s thought to bind to the active site of SIRT1.2
By interacting with these enzymes, resveratrol can influence transcription factors and thus gene expression.
Resveratrol can alter the concentration of certain proteins, some being enzymes which can:11,12,7
- Increase antioxidant activity
- Decrease apoptosis (cell death)
- Protect DNA
- Exert anti-inflammatory effects
It should be noted that the sirtuin-resveratrol mechanism is disputed by certain researchers.13
Significance? It just so happens that the dramatic effects of calorie restriction on lifespan are also attributed to the modulation of CR on the sirtuin enzymes (SIRT1 to SIRT7).
The following isn’t a detailed chart, as I didn’t include most of the nomenclature. Hopefully, it gives you a general idea.
Another mechanism having nothing to do with sirtuins is one involving the inhibition of an enzyme known as phosphoinositide 3-kinase (PI3K).14
This enzyme is involved in insulin signaling pathways and when suppressed is thought to extend lifespan.12
It also binds to and inhibits many cell-signaling molecules such as:6
- Protein kinase C (PKC)
- Aromatase (estrogen)
- Multi-drug resistance protein
- Topoisomerase II
- DNA polymerase
If that sounds like a foreign language, don’t worry. It’s not important for these purposes.
Relevance to Humans
Resveratrol has proven effective in increasing the lifespan of all species that have been tested to date. What’s unknown at this point is whether or not it lengthens the lifespan of humans. It is certainly promising.
It should be noted that while resveratrol is thought to activate the same pathways as calorie restriction, CR is much more potent in increasing lifespan. But, the upside to resveratrol is that you don’t have to starve yourself. I consider that a plus. Instead of creating a 40% calorie deficit, one need only pop a few pills.
Unlike resveratrol, the following compounds are not as strongly linked to the sirtuin (calorie restriction) pathways. There are some flimsy reports available suggesting that catechins also activate mammalian SIRT1 though to a lesser extent than resveratrol.15-17
I included them here as they do seem to promote longevity by various mechanisms and are considered by some to be CR mimetics.
The most popular catechin is a molecule with the very convoluted name of (–)-epigallocetechin-3-gallate. Yes, the infamous EGCG from green tea.
Like resveratrol, it exerts cancer preventative, neuroprotective, and cardioprotective effects.
Among its many positive effects include:18-22
- Antioxidative properties
- Suppression of cytochrome P450 enzymes (liver enzymes)
- Induction of apoptotic pathways
- Remodeling of chromatin—the material in chromosomes are composed of including protein, DNA, and RNA
- Anti-inflammatory activities
- Inhibition of angiogenesis
Other catechins are listed in the chart below.
Benefits of EGCG and Other Catechins
Catechins are flavonoids that are found in abundance in teas, specifically green tea. Polyphenols, in general, are superabundant in green tea, accounting for about 30-45% of solid extract.23
As mentioned above, EGCG is the most notable when it comes to health benefits:24-26
- Increases the survival of cells.
- Direct antioxidant activity—many phytochemicals reduce oxidation indirectly, but EGCG and other catechin derivatives act as antioxidants directly.
- Indirect antioxidant activity—EGCG and other catechins activate antioxidant enzymes.
- Activation of transcription factors
- Chelation of metal groups. Chelation just means to grab or to bind. So, these compounds can “grab” heavy metal toxins for removal from the body. Specifically, it neutralizes the ferric ion converting it to inactive iron, protecting the body from oxidation.
If you read the articles on breast or prostate cancer, then you know that isoflavones, specifically genistein are superstars in the phytochemical scene.
Genistein is the most abundant isoflavone in soy foods.
It promotes longevity by helping prevent many of the age-related diseases.27
Like resveratrol, it’s safe, even at very high concentrations.28,29
Because the compound is abundant in soy foods, it’s thought to potentially account for some of the lower rates of breast and prostate cancer seen in East Asian countries.30
Not only does it help prevent breast and prostate cancers, but genistein also protects against UV-B induced melanoma, reducing melanoma incidence.31
Some of the specific ways in which it helps prevent cancer include:31,35
- Stimulation of melanin production
- Arresting of cell growth and proliferation
- Halting of cell cycle progression
- Suppression of angiogenesis* and tumor invasion
- Lowers blood pressure
*Angiogenesis is the development of new blood vessels—a process you want to stop when it comes to the vascularization of tumors.
Mechanism of Action
It’s thought to involve:31,32
- The inhibition of protein tyrosine kinase activities
- Down-regulation of the expression of various genes, including the VEGF gene involved in angiogenesis
- Alters expression of certain antigens helping boost immunity.
- Alters genes involved in blood pressure regulation. Drinking soy milk over time can lower blood pressure in mild to moderate hypertension
The Benefit of Whole Food
The above stuff is promising, but for now, whole food is where it’s at. Why? Because we know that it works. The fact that whole plant foods improve health and longevity is empirically true, not just some fancy theory. You can see the effects when you look to the worlds’ healthiest populations.
And keep in mind that:33,34
- The above barely scratches the surface. I just named a handful of molecules, while there are over 35,000 different species of fruits, veggies, and nuts alone where one can consume more than 4,000 different flavonoid compounds
- Don’t forget nutrient synergy. As we know by now, phytochemicals and antioxidants seem to work in synergy with each other. Something you can’t get from isolated compounds. Who knows, maybe one day an isolated plant compound—or a synthetic version of it—will be able to produce amazing effects on its own, but thus far whole plant foods prove to be the most effective when it comes to human longevity.
As for significant calorie restriction (30-40% deficit), it would probably be effective, but it would also be very difficult to pull off in the long run.
Intermittent fasting is looking pretty promising in that it seems to stimulate some of the same pathways as CR and resveratrol. Maybe I’ll write on that at some point.
- Howitz, K. T. and Sinclair, D. A., 2008. Xenohormesis: sensing the chemical cues of other species. Cell 133, 387–391.
- Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., Zipkin, R. E., Chung, P., Kisielewski, A., Zhang, L. L., Scherer, B. and Sinclair, D. A., 2003. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191–196.
- Lamming, D. W., Wood, J. G. and Sinclair, D. A., 2004. Small molecules that regulate lifespan: evidence for xenohormesis (Review). Mol Microbiol 53, 1003–1009.
- Corson, T. W. and Crews, C. M., 2007. Molecular understanding and modern application of traditional medicines: triumphs and trials. Cell Metab 130, 769–774.
- Baur, J. A. and Sinclair, D. A., 2006. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5, 493–506.
- Harikumar, K. B. and Aggarwal, B. B., 2008. Resveratrol: a multitargeted agent for age-associated chronic diseases. Cell Cycle 7, 1020–1035.
- Gross, D. N., van den Heuvel, A. P. and Birnbaum, M. J., 2008. The role of FoxO in the regulation of metabolism. Oncogene 27, 2320–2336.
- Yamamoto, H., Schoonjans, K. and Auwerx, J., 2007. Sirtuin functions in health and disease: review. Mol Endocrinol 21, 1745–1755.
- Zhang, J., 2006. Resveratrol inhibits insulin responses in a SirT1-independent pathway. Biochem J 397, 519–527.
- Alvira, D., Yeste-Velasco, M., Folch, J., Verdaguer, E., Canudas, A. M., Pallàs, M. and Camins, A., 2007. Comparative analysis of the effects of resveratrol in two apoptotic models: inhibition of complex I and potassium deprivation in cerebellar neurons. Neuroscience 147, 746–756.
- Burgering, B. M. T. and Kops, G. J. P. L., 2002. Cell cycle and death control: long live Forkheads. Trends Biochem Sci 27, 352–360.
- Morris, B. J., 2005. A forkhead in the road to longevity: the molecular basis of lifespan becomes clearer. J Hypertens 23, 1285–1309.
- Pirola, L. and Fröjdö, S., 2008. Resveratrol: one molecule, many targets. IUBMB Life 60, 323–332.
- Fröjdö, S., Cozzone, D., Vidal, H. and Pirola, L., 2007. Resveratrol is a class IA phosphoinositide 3-kinase inhibitor. Biochem J 406, 511–518.
- Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, L Zhang L, Scherer B, Sinclair DA. Nature. 2003;425:191–196.
- Davis JM, Murphy EA, Carmichael MD, Davis B. Am J Physiol Regul Integr Comp Physiol. 2009;296:R1071–R1077
- de Boer VC, de Goffau MC, Arts IC, Hollman PC, Keijer J. Mech Ageing Dev. 2006;127:618–627
- Dashwood, R. H., Myzak, M. C. and Ho, E., 2006. Dietary HDAC inhibitors: time to rethink weak ligands in cancer chemoprevention? Carcinogenesis 27, 344–349.
- Mattson, M. P. and Cheng, A., 2006. Neurohormetic phytochemicals: low-dose toxins that induce adaptive neuronal stress responses. Trends Neurosci 29, 632–639.
- Myzak, M. C. and Dashwood, R. H., 2006. Histone deacetylases as targets for dietary cancer preventive agents: lessons learned with butyrate, diallyl disulfide, and sulforaphane. Curr Drug Targets 7, 443–452.
- Juge, N., Mithen, R. F. and Traka, M., 2007. Molecular basis for chemoprevention by sulforaphane: a comprehensive review. Cell Mol Life Sci 64, 1105–1127.
- Morris, B. J., 2008. How xenohormetic compounds confer health benefits. In Le Bourg, E., Rattan, S. I. S. (eds), Mild Stress: Applying Hormesis in Aging Research and Interventions. Springer, Amsterdam, Netherlands, pp. 115–138.
- Wang, Z. Y., Huang, M. T., Lou, Y. R., Xie, J. G., Reuhl, K. R., Newmark, H. L., Ho, C. T., Yang, C. S. and Conney, A. H., 1994. Inhibitory effects of black tea, green tea, decaffeinated black tea, and decaffeinated green tea on ultraviolet B light-induced skin carcinogenesis in 7,12-dimethylbenz[a]anthracene-initiated SKH-1 mice. Cancer Res 54, 3428–3435.
- Mandel, S. A., Avramovich-Tirosh, Y., Reznichenko, L., Zheng, H., Weinreb, O., Amit, T. and Youdim, M. B., 2005. Multifunctional activities of green tea catechins in neuroprotection. Modulation of cell survival genes, iron-dependent oxidative stress and PKC signaling pathway. Neurosignals 14, 46–60.
- Higdon, J. V. and Frei, B., 2003. Tea catechins and <polyphenols: health effects, metabolism, and antioxidant functions. Crit Rev Food Sci Nutr 43, 89–143.
- Grinberg, L. N., Newmark, H., Kitrossky, N., Rahamim, E., Chevion, M. and Rachmilewitz, E. A., 1997. Protective effects of tea polyphenols against oxidative damage to red blood cells. Biochem Pharmacol 54, 973–978.
- Cassidy, A., 2003. Potential risks and benefits of phytoestrogen-rich diets. Int J Vitam Nutr Res 73, 120–126.
- Bloedon, L. T., Jeffcoat, A. R., Lopaczynski, W., Schell, M. J., Black, T. M., Dix, K. J., Thomas, B. F., Albright, C., Busby, M. G., Crowell, J. A. and Zeisel, S. H., 2002. Safety and pharmacokinetics of purified soy isoflavones: single-dose administration to postmenopausal women. Am J Clin Nutr 76, 1126–1137.
- Busby, M. G., Jeffcoat, A. R., Bloedon, L. T., Koch, M. A., Black, T., Dix, K. J., Heizer, W. D., Thomas, B. F., Hill, J. M., Crowell, J. A. and Zeisel, S. H., 2002. Clinical characteristics and pharmacokinetics of purified soy isoflavones: single-dose administration to healthy men. Am J Clin Nutr 75, 126–136.
- Park, O. J. and Surh, Y. J., 2004. Chemopreventive potential of epigallocatechin gallate and genistein: evidence from epidemiological and laboratory studies. Toxicol Lett 150, 43–56.
- Ravindranath, M. H., Muthugounder, S., Presser, N. and Viswanathan, S., 2004. Anticancer therapeutic potential of soy isoflavone, genistein. Adv Exp Med Biol 546, 121–165.
- Rivas, M., Garay, R. P., Escanero, J. F., Cia, P., Jr., Cia, P. and Alda, J. O., 2002. Soy milk lowers blood pressure in men and women with mild to moderate essential hypertension. J Nutr 132, 1900–1902.
- Howes, M. J. and Houghton, P. J., 2003. Plants used in Chinese and Indian traditional medicine for improvement of memory and cognitive function. Pharmacol Biochem Behav 75, 513–527.
- Howes, M. J., Perry, N. S. and Houghton, P. J., 2003. Plants with traditional uses and activities, relevant to the management of Alzheimer’s disease and other cognitive disorders. Phytother Res 17, 1–18.
- Sarkar, F. H. and Li, Y., 2002. Mechanisms of cancer chemoprevention by soy isoflavone genistein. Cancer Metastasis Rev 21, 265–280.
- Anderson, R. M., Bitterman, K. J., Wood, J. G., Medvedik, O. & Sinclair, D. A. Nicotinamide and Pnc1govern lifespan extension by calorie restriction in S. cerevisiae. Nature 423, 181–185 (2003).