Free Radicals in AgingMarch 30th, 2021
By Richard Lippman, Ph.D.
Today, we know that free radicals aren’t activists out on bail. But many decades ago, when I was doing research in Sweden, most people thought free radicals was hippie politics!
No one knew then that these molecules had devastating effects on the human body, nor of their role in aging. Indeed, even just 20 years ago, free radical chemistry and its toxic effects on the human body were unknown to much of the public and even many doctors and medical researchers.
I first learned about the free radical theory of aging as an undergraduate student at the Royal Institute of Technology in Stockholm, Sweden. After I began doing graduate research work in cell biology, myself and my colleagues held meetings and conferences at the University of Uppsala to discuss the exciting findings of Professor Denham Harman, whose experimental work at the University of Nebraska in the 1950’s showed mice life spans could be extended 50 percent with antioxidant supplementation. And the response of the press was? So, what!
Raising funds for research
I wanted to take Harman’s work one-step further and explore the relationship between free radicals and aging. I turned to the famous Professor Sven Brolin, chair of the University of Uppsala’s Department of Medical Cell Biology, and to Professor Gunnar Wettermark, chair of the Royal Institute of Technology’s Department of Physical Chemistry, for assistance in raising funds for research.
Eventually, I received significant medical and chemical grants from the Swedish Research Council to develop antiaging strategies based on Harman’s groundbreaking discovery of the action of free radicals and the role of antioxidants to inhibit them.
That research took us into the role that free radicals play in the breakdown of aging human bodies and led to the development of one of the most potent antioxidant combinations yet known, a unique multilevel antioxidant cocktail called ACF228® (ACF = Aging Control Formula). This remarkable work resulted in a US patent, number 4,695,590 (1) and encouraged the publication of the book Stay 40 (2) as well as many scientific articles in leading medical journals (3, 4, 5).
A cellular model
The first task of the research team was to find a cellular model rather than an animal model to test for life extension, since the Harman model of waiting for mice to grow old and die was costly and took years of patience.
At the department of Medical Cell Biology, the team had access to many different types of living cells in culture; cells of the heart, brain, liver, and central nervous system and I invented some special probes that would penetrate the cell interiors without harming them. The first probe, called CML (carnitinylmaleate luminol), measured superoxide radicals in live human liver cells (3, 4). We went on to test many different combinations of regenerative nutrients and hormones as was later reflected in ACF228®.
We were able to measure ATP activity down to femtogram (ten to the minus fifteen) amounts in actively respiring individual human cells (4). From these instruments, and others, such as a unique near-infrared spectrometer that measured lipid peroxides in volunteers without drawing their blood, the research allowed us to measure free radical activity in vivo and non-invasively in people, plus their antioxidant status that defended against these radicals.
Subsequently, the cell cultures were impregnated with special CML probes and incubated with different mixtures of vitamins, hormones, and known regenerative nutrients. Eventually, 228 different mixtures were tested to find an optimal mixture, which encouraged longevity-promoting characteristics. Thus, formula 228 was found to work best, and this was tested further in vivo in mice, dogs, and humans. The cumulation of US patent number 4,695,590 is the only patent granted by the US Patent Office with claims to slow human aging. Furthermore, note that other promoters of antioxidant products have not tested their product in vivo. Instead, they were only tested in vitro that means ‘in a test tube.’ Indeed, it was discovered that vitamins are often too weak to effectively quench (render harmless) free radicals and reactive oxygen species. For this reason, we tested and patented the exceptionally strong antioxidant nordihydroguaiaretic acid (NDGA) found within ACF228®.
The final formulation was later tested by three US government laboratories under the auspices of the National Institute on Aging (NIA) in Washington, D.C. In 2003, the NIA concluded that ACF228® increased mice longevity by an average of 12 percent.
How does ACF228® prevent aging?
Every day we breathe kilograms of oxygen that is converted into grams of free radicals and downstream reactive oxygen byproducts. We have natural defenses to render harmless this ongoing cascade of damages resulting in many aspects of aging. For example, our three natural defenses are:
- The enzyme catalase that destructs hydrogen peroxide to harmless water and oxygen.
- The body’s primary antioxidant, glutathione, that destructs hydroxyl radicals to harmless hydroxy byproducts.
- Superoxide dismutase, that destructs superoxide to oxygen.
However, our natural defenses are insufficient to counter free radicals as we age. We need other multilevel boosters to counter the relentless, ongoing cascade of strong, weak, and medium-strength radicals and their byproducts.
Each of these three types of radicals required a multilevel variety of antioxidants to counter each type of toxin individually. This multilevel variety is included in the patented ACF228® formula (see figure one).
Figure One: A diagram of the multilevel effects of aging caused by free radicals and active oxygens as well as their natural and supplemental quenchers and destructors. Unfortunately, epigenetic modifications and hormone replacement therapies do not solve free radical damages causing aging. Both have their limitations in slowing and reversing aging.
In other words, free radical cascades flood into our cells like bombs, and the long-term collateral damages are significant. We call these ongoing collateral damages ‘aging.’
Free radicals, aging and Alzheimer’s
Age spots are usually caused by oxidation or peroxidation of proteins and oils, and we notice them as discolored brown spots on the skin of seniors. If seniors consume a balanced and multilevel variety of antioxidants such as those contained in ACF228®, age spots will often disappear, at least temporarily, until newly oxidized or peroxidized waste products and their odd smell again appear on the skin.
To help understand the chemical process that cause these spots, consider the browning of apples and bananas. They gradually become brown when exposed to the oxygen in the air. Another example of this browning process is found in the progressive rancidness of nuts if they are not vacuum packed. Nuts exposed to the open air become rancid, and this process is exactly what is occurring in our bodies, that is if a balanced diet of antioxidants is not consumed in the form of sensible food and a variety of supplements.
Toxic byproducts in our skin caused by aging
During aging and especially after the age of forty, our skin emits tiny amounts of a smelly and rancid oil called nonenal that is unpleasant to inhale. Nonenal is an aldehyde related to formaldehyde, an embalming fluid. Another disgusting aldehyde is acetaldehyde that emits a pungent and nasty smell. It is easily detected when in the same room with a sleeping person who has consumed excessive amounts of alcoholic beverages.
Historically, perfumes and skin lotions were invented to hide aldehyde smells that occur because of aging and dysbiosis. Before we emit nonenal odors during our forties and older, we are naturally producing odiferous sex hormones such as testosterone in men and estradiol in women. Men notice women with high levels of estradiol, and women notice men with high levels of testosterone. This effect causes attraction between the sexes and procreation of humanity. However, when pungent smelling nonenal enters the picture after age forty, the attraction smells of sex hormones are blunted. Perhaps this was Mother Nature’s way of promoting procreation among the young but not among the old?
You may wonder how we can identify nonenal? Nonenal is noticeable if you ever visit a nursing home where it is referred to as ‘old-people smell.’ Consuming L-carnosine and acetyl-l-carnitine at bedtime will neutralize and prevent the skin’s formation of nonenal. Your skin will appear and smell normal and sex-hormone youthful again without the need for perfume.
A smell test for identifying premature aging
Let us consider the ACF228® smell test. On the day of testing, do not consume alcohol. Before bedtime, clean the backs of your ears with rubbing alcohol. Consume one or two capsules of ACF228®. The following morning you should not detect the smell of nonenal behind your ears or anywhere else on your person. ACF228® has quenched and eliminated the rancid smells of aging.
In conclusion, people with nonenal odors emitting from their bodies are aging prematurely, and free radicals and their downstream oxidation/ peroxidation toxins cause it.
What are the underlying causes of free radicals?
I have explored this topic in detail during many decades of research since my first scientific publication on free radicals in 1978. Interestingly, if you are generating the free radical, superoxide from heavy exercise, your mitochondrial respiratory chain is often overwhelmed, and you are leaking a large amount of this deleterious free radical into your body, including the skin.
Furthermore, there is a double whammy effect occurring internally. According to researcher Nathan S. Brown, PhD, superoxide also shuts down the production of NO or nitric oxide that is critical for the expansion and health of our arteries. In addition, there is even a third negative side effect when NO reacts with superoxide. If we restore NO production through gut bacteria or consuming beets, we will attenuate superoxide production and subsequent oxidation/ peroxidation events such as age spots and other browning spots on our skin, and perhaps, even in our brains. (6,7).
Alzheimer’s and Tau proteins in the brain
All these effects during aging brings us to another important topic: How does Alzheimer’s disease develop in relation to oxidation/ peroxidation processes occurring continually throughout our bodies and especially in our brains? It’s a well-documented fact that Tau proteins break down in the brain to lipofuscin and beta amyloid. They consist of a brown residue chemically related to brown spots on the exterior of our skin as we age. Tau proteins are three-dimensional cage-like proteins held together by several disulfide bridges. These disulfide bridges are easily damaged chemically causing folding in the Tau protein because their S-S bonds are very weak and susceptible to oxidation/ peroxidation. In summary, these disulfide bridges are easily damaged chemically, and the Tau protein cage structure folds or collapses into a mushy, foul-smelling toxin called beta amyloid.
Two-time Nobel Prize winner Linus Pauling discussed this effect personally with me and in his prize-winning book, The Nature of The Chemical Bond, 3rd Ed. 1960, Cornell University Press. He was convinced of the weakness of the Tau protein’s disulfide bonds, and their subsequent misfolding or collapse was a result of oxidation/ peroxidation (8).
I have always believed him to be correct, and thus, I embarked on a course of experiments to discover the antioxidant and prooxidant properties of vitamin C. My research was twice presented at the Pauling Institute in California. I found that 300 mg or less of C acted as an antioxidant, and this unique knowledge was included into the ACF228® formula.
On the other hand, 1,000 mg or more of C acted as a prooxidant. Therefore, this is exactly why I recommend consuming 1,000 mg of C every four hours and during the onset of the common cold. Symptoms disappear overnight when my four-hour protocol is strictly followed because the prooxidant properties of excessive C kill rhinoviruses, and cold symptoms are ameliorated. On the other hand, 300 mg or less of C helps to hold in check oxidation of proteins and oils.
In recent years, Dr. Forlenza and his research group have recommended a second method that uses microdoses of the light metal lithium to preserve the Tau protein structure. Three hundred micrograms of lithium daily is recommended to avoid Alzheimer’s and cognitive impairment. (7)
The surprising truth about greying hair
If you want an example of peroxidation damage, try pouring a tiny amount of hydrogen peroxide on your finger. After a few minutes, the skin on your finger will turn a sickly white. Then imagine that hydrogen peroxide is being produced in every cell in your body 24/7. It is often countered and rendered harmless by our large enzymatic supply of catalase (contained in ACF228®). But when catalase is lacking due to aging, one effect is the greying and whitening of our hair. And according to prominent medical authorities such as Ward Dean, MD, hair whitening is strongly correlated with our biological aging except for people who grey prematurely. In other words, when you lose your large supply of catalase during aging, your hair turns first grey and then white.
ACF228® counters this whitening and damaging effect at the cellular level. Second, at the arterial level, it prevents the hardening of our arteries. At the systemic level, it generally prevents our organs and skin from deteriorating prematurely.
ACF228® prevents us from oxidizing internally and externally. A simple test for determining your oxidation status is to examine daily the color of your stools. Light brown stools indicate low oxidation/ peroxidation status. Dark brown or black stools indicate high oxidation/ peroxidation as well as a high free radical status in your body. Thus, if your goal is optimal health, ACF228® can assist.
An optimistic and optimal health future
We should all be able to live to 120 and perhaps even beyond in optimal and exceptional health. Unfortunately, we do not receive optimal and exceptional health today from Medicare— also known as mediocre care— either from the US government or British National Health Service. One reason we don’t live to extreme age in good condition is because of the free radical damage that our cellular systems sustain.
During aging, our brain’s shrink 30 percent, our arteries become hardened, our liver and other organs functionally decline, and much of this is due to free radical pathology, loss of nutrient absorption, and hormonal decline. When our key endocrine glands shrink, we become less able to repair damages from free radicals and active oxygens. These two phenomena are what we often call the effects of aging. Unfortunately, epigenetic modifications and hormone replacement therapies do not solve free radical damages causing aging. Both have their limitations in slowing and reversing aging.
Aging is the enemy of health and the ultimate disease and ACF228® with its unique blend of antioxidants, radical scavengers, membrane preservatives and nutrients can help people prevent aging’s premature onset.
Today, I continue my medical research focusing on improved methods of repair using nutrition, peptides, and hormone corrective therapies that also include DIM, carnosine, and resveratrol.
Repairing the body after free radical damage is the second half of the equation that allows us to slow and reverse our aging.
- Lippman, R., S. Patent Numbers 4,695,590 & 15 401 076.
- Lippman, R., Stay 40, 2008, Outskirts Press, Boulder, CO.
- Lippman, R., Experimental Gerontology, 1980, “Chemiluminescent measurement of free radicals and antioxidant molecular protection inside living rat mitochondria,” vol. 15.
- Lippman, R., Experimental Gerontology, 1985, “Rapid in vivo quantification and comparison of hydroperoxides and oxidized collagen in aging mice, rabbits, and man,” vol. 20.
- Lippman, R., Journal of Gerontology, 1981, “The Prolongation of Life” A Comparison of Antioxidants and Geroprotectors Versus Superoxide in Human Mitochondria,” vol. 36, nr. 5, pp. 550-557.
- Tjero, J. et al. Sources of Vascular Nitric Oxide and Reactive Oxygen Species and their Regulation. Physical Rev. 2019 Jan. 1, 99(1):311-79.
- Forlenza OV, Diniz BS, Radanovic M, et al. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomized controlled trial. Br J Psychiatry. 2011 May; 198(5):351-6.
- Mossuto, M. F., 2013, International J. of Cell Biology, Disulfide Misfolding in Neurodegenerative Diseases,