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How the world got lost on
the road to an anti-aging pill
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September 8, 2019: by Bill Sardi
There is a new leader in anti-aging science and his schooling is not in genetics or biology but rather statistics and mathematics.
Step aside David Sinclair PhD, Harvard Medical School geneticist who in 2004 announced the discovery of the Sirtuin1 gene, which is activated by a lifespan prolong calorie-restricted diet and by resveratrol, a molecule found in red wine, a discovery that explained the French Paradox – why the wine-drinking French have higher cholesterol numbers but far fewer heart attacks than North Americans.
Take a backseat in the lecture hall Leonard Guarente, PhD at MIT who in 2014 introduced a designer niacin-like molecule that also activates the Sirtuin1 survival gene and serves as an anti-aging pill.
Advocates of the telomere theory of aging are now silent. Shortening of telomeres has been theorized as a measure of human aging. Telomeres are end caps on chromosomes, bundles of DNA. While shortening of telomere length is a marker of oxidation, it is not necessarily a marker of aging.
The new front-runner in the race to explain why humans age is Steve Horvath PhD, UCLA professor who has developed the Horvath Clock, a highly accurate marker of aging.
The history of science of life extension dates back into the 1800s. The world’s first conference on aging and longevity was held in Kiev in 1938. Up till now, many theories of aging abound but there is no scientific consensus over its dominant cause. Horvath’s biological clock is about to surge ahead of other predominant explanations for human aging.
Dr. Horvath is making worldwide news headlines for a discovery that it may be possible to reverse human aging, not just slow it down.
The use of a growth hormone plus two anti-diabetic drugs helped to regenerate the thymus gland which normally shrinks with advancing age and weakens the immune system. The big discovery however was all of the men in a small study group who were given these medicines had fewer methyl groups tagged onto their DNA (this will be explained below). Biologically these men were 2.5 years younger after 1-year on the test medicines. That was totally unexpected says a report in Nature Magazine.
Horvath relied upon his Horvath Clock which is considered the most reliable tool for measuring the biological age of an individual compared to chronological (calendar) age. Three other “biological clocks” were also utilized in his analysis.
Following the discovery of DNA in 1953, this blueprint of ourselves that is housed in every living cell, became the focus of anti-aging research. Initially geneticists thought the inherited makeup of DNA and sequences of steps on the DNA ladder (called nucleotides) governed longevity. But the most recent analysis published in the journal Genetics shows only about 7 percent of people’s lifespan is determined by genetics. Mis-sequenced or missing nucleotides on DNA would represent mutations which would only reduce, not prolong, human lifespan.
The fact that human longevity tends to run along family lines misleadingly suggested inheritance prevailed as far as longevity is concerned.
But longevity can also be familial, which is confused with inherited traits. Families tend to eat the same food, drink the same water, be exposed to the same amount of sunshine, etc. These environmental factors govern what is called epigenetics – the way genes respond to surrounding factors by either making proteins (gene expression) or not making proteins (gene silencing).
Mild biological threats or stressors, such as exposure to mild forms of radiation, modest cold or hot temperatures, or food deprivation (calorie restriction or fasting), activate survival genes. For example, food deprivation (calorie restricted diets) doubles the lifespan of laboratory animals. This was proven by Dr. Clive Mackay in the 1930s and then further confirmed by Roy Walford and Richard Weindruch in the 1980s.
Molecules like resveratrol that activate the same genes as a calorie restricted diet can also be used as anti-aging pills. No self-discipline needed.
It must be noted that resveratrol desirably decreases DNA methylation. Methylation is technically described as a transfer of a methyl CH3 group to a cytosine nucleotide. Don’t get lost in the science here. The graphic below will help you grasp an understanding of what anti-aging researchers are talking about.
A methyl (CH3) is attached to DNA to alter its activity without changing the sequence of the steps (nucleotides) on the DNA ladder. An alteration of the sequence of DNA nucleotides would comprise a mutation.
DNA methylation is a way of altering the protein-making activity of genes. Methylation signals a gene to an “off” position, also called gene silencing.
Methylation is part of what is called epigenetics. DNA methylation age reflects that the biological age of a person and differs from chronological (calendar) age.
The steps on the DNA ladder are comprised of four proteins (nucleotides): cytosine (C), guanine (G), thymine (T) and adenine (A), the so-called letters of the DNA ladder.
Methylation of DNA occurs at a site on strands of DNA where cytosine (C) lies next to guanine (G) in the DNA sequence. This is called a CpG site. (See graphic above.)
The Horvath Aging Clock monitors 353 of the CpG sites on DNA. CpG sites are predominantly nonmethylated. A small fraction of CpG sites on DNA are either methylated or demethylated with advancing age.
As Dr. Horvath convincingly demonstrates, methylation at CpG sites on the DNA strand is the most accurate way of predicting mortality in humans.
Acceleration of DNA methylation age predicts risk of age-related disorders. Therefore, it is not a surprise to learn that DNA methylation effectively predicts the risk of future heart attacks and heart disease.
Don’t try to fully understand DNA methylation because it is a complicated science. Suffice to say, epigenetic clocks based on the dynamic methylation of certain CpG sites on DNA during aging are the most accurate way to distinguish chronological from biological age. To slow or even reverse aging, demethylation is the objective.
The following graphic will help you understand DNA methylation.
Source: Frontiers in Genetics Feb. 18, 2019
In recent months a biological phenomenon called cell senescence has catapulted into public attention. Over time some cells cease replicating, become a source of inflammation and result in frailty in older individuals. Fisetin, a natural molecule found abundantly in strawberries, was found to eradicate zombie senescence cells in a superior manner to other natural molecules and extended lifespan of laboratory animals. Drugs that would overcome cell senescence are now considered an emerging new direction in anti-aging medicine.
However, epigenetic aging has been found to be distinct from cell senescence. Horvath diminishes the importance of cell senescence as far as promoting longevity (read more below).
Horvath developed a multi-tissue predictor of age that allows an estimation of the DNA methylation age of most tissues and cell types.
It has been demonstrated in animals that the antibiotic (doxycycline) restores the youthful activity and DNA methylation of just three genes to promote regeneration of the optic nerve. Regenerative capacity was retained in aging cells to restore youthful function and age reversal despite experimental destruction of the optic nerve. This was accomplished without stem cell injection.
Doxycycline and its forerunner tetracycline have been shown to be iron chelators (binders). To the contrary, the provision of doxycycline to young growing mice induces premature aging, as iron is required for growth and development.
Consistent with the overmineralization theory of aging, Horvath reports that menopause (the cessation of menstrual loss of iron-rich blood) is associated with biological aging. Using the Horvath “epigenetic clock,” menopause accelerates the epigenetic aging process.
This suggests the time to employ anti-aging pills is when full childhood growth is achieved in males (~ age 18) and with the onset of menopause in females (~age 45+).
An interview with Steven Horvath at the FIGHTAGING.com website is telling:
Why is the epigenetic clock more accurate than measuring telomere length?
“Yes, it is far more accurate, there is no comparison. “Why?” is a good question. In my opinion, it shows that epigenetic changes are far more important for aging than telomere maintenance. People have studied telomeres for many years, including me, but telomere shortening alone does not explain aging. You may know that mice have perfect telomeres, but they only live an expected three years.”
“Removal of senescent cells, which contribute to inflammation, would surely impact the epigenetic clock somewhat, though I wager not that much. It will not stop global demethylation and that is the main point – aging will continue; … the inflammatory causal element of the cells will be removed; but that will not stop the aging global demethylation process which correlates to epigenetic age.”
DNA methylation is one of the most important chemical signals in the human body. Ways of thwarting unwanted methylation have been identified.
Turning back the clock hands of biological time has been reported prior to Horvath’s recent published report. In 2016 researchers at the Salk Institute report Intermittent control of epigenetic factors was able to turn “old cells back to their embryonic state and reverse the hallmarks of old age.” Lifespan was increased by 30%.
Horvath has shown by altering the activity of four specific genes that are known to convert adult stem cells into stem cells that can differentiate into muscle, brain, skin, liver, blood cells (aka pluripotent stem cells), he could “completely reverse: epigenetic aging. Horvath was able to reset the biological age of these skin cells to an epigenetic age that “was the age of a fetus.” Biologically, age zero!
In another landmark study published in January of 2019 that preceded the current Horvath study now making news headlines in September of 2019, 4000 IU vitamin D supplementation was employed among overweight and obese subjects which resulted in 1.85 years decrease in Horvath epigenetic aging compared with placebo. The Horvath study now making news headlines was not controlled with a placebo comparison. So, this study has more validity yet it is being overlooked.
In humans it took a year for the 2.5 years of de-aging to take place. In laboratory animals, activation of longevity genes slowly increase over time in calorie-restricted animals compared to animals fed a normal calorie diet.
In laboratory mice, over a period of about three years 831 longevity genes are progressively differentiated by a limited calorie (limited minerals) diet, about 277 genes a year.
In the short-term (12 weeks) after weaning of laboratory mice, a calorie restricted diet differentiated 198 longevity genes, resveratrol (a molecular mimic of calorie restriction) 225 genes, and Longevinex®, a commercially available complex of resveratrol + other polyphenols activated 1711 longevity genes. It is apparent a complex of anti-aging molecules can produce a more demonstrable and rapid activation of anti-aging genes.
Now we all don’t want to go back to a fetal stage brain-wise. Facetiously, via DNA methylation could we turn back the clock hands of time so adults would become infants again? If so, we might all suffer the same fate as the incredible shrinking man as seen in the movie by the same title.
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