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Small Molecules Poised To Alter Course Of Humanity.

Given the assumption humanity is not going to deprive itself of food to live an extra 40-50 healthy years (healthspan and lifespan doubles among calorie restricted animals), biological short cuts in the form of molecular mimics of calorie restriction appear more practical. Widespread use of properly dosed small molecules could achieve super-longevity only rivaled by the Biblical patriarchs.

Mild biological stress activates cellular defenses. Small molecules, as presented here, that can pass through cell walls and enter the nucleus and favorably influence genetic machinery are abundant in nature. Cells with a mass of less tan 100 nanometers (billion of a meter) in one direction can absorb molecules and pass through the blood/ brain barrier. [Nanomedicine 2011] Many natural molecules already are smaller than 100 nanometers and don’t require nanosizing to enter cells. [Knowledge of Health]

Small Molecules	Natural Source	Molecular weight grams/mole
Resveratrol	Grape wine	228.25
Berberine	Oregon grape	336.36
Apigenin	Celery	270.24
Tocotrienols (delta)	Palm	396.60
Curcumin	Turmeric spice	368.38
Quercetin	Onion, apple	302.23
Ferulic acid	Rice bran	194.18
Eugenol	Clove oil	164.20
EGCG	Green tea	458.37
Capsaicin	Red pepper	305.41
Allicin	Garlic	162.27
Thymoquinone	Black cumin	164.20

Many of these small molecules are available today as herbal extracts and so far have outperformed synthetic analog (look-alike) molecules that pharmacologists have schemed to profiteer. [Ageing Research Reviews 2009; Nature Medicine 2015]

While researchers attempt to develop synthetic analogs (molecular look-alikes) of these natural molecules, their efforts may be futile. Adding a molecular tail to obtain a patent may not be meaningful biologically. For example, efforts to produce a molecular analog of resveratrol were thwarted by the fact resveratrol via liver metabolism regenerates back to the form of the parent molecule after its absorption makes synthetically-made resveratrol-like molecules almost laughable. [Molecular Pharmacology 2013]

The Biblical patriarchs were not likely to have universally ingested small molecules to achieve their longevity, though unfiltered wine would have provided a sufficient dose to achieve long life at that time. Unfiltered wine provides ~30 times more small polyphenolic molecules (resveratrol, quercetin, ferulic acid, etc.) than modern refined and filtered wines produced today and would have acted as an anti-aging pill.

The presumed superlongevity of the Biblical patriarchs more likely emanated from universal exposure to mild biological stress from ground sources when terrestrial radiation (radon gas) was harsher. [Radiation Protection Dosimetry 2015; Journal Cell Communication Signaling 2014]

Essentially, all of the small molecules identified as mimics of calorie restriction when provided in modest doses promise anti-aging effects as mild biological stressors. While posed as antioxidants, they provoke a pro-oxidant response initially, triggering defensive measures within living cells. [Neurochemical Research 2008]

Desirable defensive responses to mild biological stress, such as posed by selected small molecules, is known as hormesis. Low-dose exposure to these biological stressors, below toxic dose, produces a beneficial effect. [Ageing Research Reviews 2008] A gene transcription factor called Nrf2, triggered by exposure to mild biological stress, activates protective endogenous (internal) antioxidants (glutathione, catalase, superoxide dismutase, heme oxygenase). [Dose Response 2007]

Biologists already know the genes involved in anti-aging effects. These genes and gene transcription factors are mTOR, AMPK, NF Kappa B, Sirtuin 1, FOXO and Nrf2. Mother Nature provides a growing list of small molecules that influence these epigenetic (protein-making) factors, as listed in the following chart. A description of each of these gene factors is provided at the end of this report.

NATURAL MOLECULES: INFLUENCE OVER KEY ANTI-AGING GENES
Natural source	Molecule	mTOR	AMPK	NF Kappa B	Sirtuin1	FOXO	Nrf2
Grape wine	Resveratrol	X	X	X	X	X	X
Oregon Grape	Berberine	X	X	X	X	X	X
Celery	Apigenin	X	X	X	ND	X	X
Palm oil	Tocotrienols	X	X	X	ND	ND	X
Turmeric	Curcumin	X	X	X	X	X	X
Red onion/apple	Quercetin	X	X	X	X	X	X
Rice bran	Ferulic acid	X	X	X	ND	ND	X
Clove bud oil	Eugenol	X	X	X	ND	ND	X
Green tea	EGCG	X	X	X	X	X	X
Red pepper	Capsaicin	X	X	X	X	X	X
Garlic	Allicin	X	X	X	X	X	X
Black cumin seed oil	Thymoquinone	X	X	X	ND	X	X
ND= no data reported Source: Bill Sardi, Knowledge of Health, Inc.

Dosing studies to achieve a low-dose hormetic effect are few. What is gleaned from studies involving wine is that 3-5 glasses of dark-red aged wine (providing ~60 mg polyphenols per 5-oz. glass), or 180-300 mg of total polyphenols, dramatically reduces mortality from coronary artery disease. [Biological Research 2004; Nature 2006]

The late Dipak Das PhD, conducted studies in the animal lab, which correlated with the above numbers. The human equivalent of 175-350 milligrams of resveratrol protected heart muscle from damage during an intentionally induced heart attack in laboratory mice, with a 10-fold greater dose (1750-3500 mg) resulting in greater damage to heart muscle tissue. [Experimental Clinical Cardiology 2010]

Based upon limited experimental and population data, the total dosage range of small molecules, both from diet and supplements, would be in the range of 175-350 milligrams/day to achieve hormesis and longevity via Nrf2 mechanisms. A lesson here is that more is not better. — ©2015 Bill Sardi, ResveratrolNews.com

mTOR: stands for mechanistic target of rapamycin. mTOR is the primary gene target of rapamycin, produced from the soil organism Streptomyces hygroscopicus. Rapacmycin is an antifungal antibiotic that inhibits mTOR and extends life. Rapamycin is commonly prescribed to inhibit autoimmune rejection of organ transplants.

AMPK: a cell-energy sensing enzyme (5′ adenosine monophosphate-activated 5′ AMP-activated protein kinase). AMPK is a master regulator that is activated in response to low energy (ATP) levels, low glucose, shortages of cellular oxygen. Molecular activation of AMPK is desirable for metabolic health.

NF Kappa B (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein that control transcription of DNA, and is involved in initial responses to biological stress such as threats posed by radiation, oxygen free radicals, inflammatory factors (cytokines), and germs. Inhibition of NF Kappa B controls inflammation. Since low-grade inflammation is a hallmark of aging, inhibition of NF Kappa B is considered an anti-aging strategy.

Sirtuin 1: known as a survival gene, it is activated during biological stress, such as when food is in short supply. Therefore, it is not surprising that a calorie restricted diet activates this gene. In the animal lab, calorie restricted mice live about twice as long as mice fed a regular diet.

FOXO are gene transcription factors that regulate metabolism, stress tolerance and lifespan. FOXO gene proteins play a role in promotion of tumor suppression and longevity. FOXO proteins reside in the cytoplasm of living cells and translocate to the cell nucleus to trigger cellular responses that result in lifespan extension.

Nrf2 is a protein that resides in a latent state within each cell in the body that activates endogenous (internal) enzymatic antioxidants in response to biological stress. Mild biological stress activates Nrf2, which in turn activates glutathione, catalase, super oxide dismutase and heme oxygenase, protective antioxidants. Molecules that activate Nrf2 are mild biological stressors would serve to place the body on alert in an antioxidant protective mode. In the laboratory, animals given Nrf2 activators are protected from tissue damage caused by strokes or heart attacks. While molecular activation of Nrf2 is desirable for prolonged life, excessive doses become toxic rather than protective. Nrf2 activators must be delivered in modest doses. [Aging Cell 2015]