As I described in a previous article on dietary guidelines, science is a process of continuous improvement1. This month, I am describing an exciting example of this. In a recent study, researchers tried to regenerate and reactivate the thymus gland in healthy aging men2. The thymus gland produces immune cells (T-cells) that protect us from diseases, including cancer and heart disease. However, it decreases in size as we age, resulting in a weakened immune system. The researchers were successful in regenerating and reactivating the thymus gland, but at the same time they made a startling observation. Several biomarkers of aging indicated that the aging process had been reversed2. So, the goals of my article this month are to tell how scientists try to measure aging and give an example of how careful observation during one experiment led to an unexpected discovery that subsequently can be tested clinically. That is, a combination of recombinant human growth hormone (rHGH), the dietary supplement dehydroepiandrosterone (DHEA) and the prescription drug metformin was apparently able to reverse aging and the development of senescence in the neuroendocrine immune systems in people who participated in the clinical trial2.
Intelligence is one of our greatest strengths and weaknesses. It enables us to recognize our mortality, while fooling us into thinking that we can live healthy lives forever. People have been looking for ways to reverse aging for thousands of years. The ancient Greek historian Herodotus wrote about a Fountain of Youth in the 5th century BCE. The Spanish explorer Juan Ponce de León was searching for the Fountain of Youth when he claimed Florida for the Spanish empire.
The search for ways to reverse aging continues today. Some say it can’t be done, while others claim that they are already doing it. There are dietary supplements, human growth hormone (HGH) and even a prescription drug (metformin) that some claim can slow down or even reverse aging. At the same time, experts are continuously improving our understanding of what causes aging. Systems thinkers are using all their resources to help improve public health and save lives. They use both observation and hypothesis-driven research to come up with solutions. Some of the most important medical discoveries in history were based on careful observations of phenomena that were not expected. In modern medicine, many prescription drugs were developed by identifying a therapeutic target and testing a hypothesis. The hypothesis is often that a new chemical entity (NCE) or natural product will bind to a therapeutic target, such as an enzyme or a protein receptor. For example, there are several genes that can become mutated and produce proteins that can cause cancer (oncogenes and oncoproteins). If these genes and proteins are essential for cancer cells to survive, then the NCE or dietary supplement would be expected to be effective and kill the cancer cells. Once the basic scientific principal is proven, clinical trials can begin. However, the objective or endpoint of the clinical trials is not how effective the NCE or dietary supplement is at inhibiting an enzyme or antagonizing a receptor. Instead, the goal of these studies is to extend the lifespan of the subjects or eliminate a risk factor (like disappearance of a biomarker in the blood).
How scientists try to measure biological age
Before we can find out if something reverses aging, we should develop the best method possible for measuring one’s biological age, which is different than chronological age. That is, two people who were born on the same day and have the same chronological age could have very different biological ages and therefore different lifespans. Obesity, chronic inflammation, stress and diseases can make one person have fewer healthy years of life (healthspan) and die sooner (shorter lifespan, increased mortality). To help estimate healthspan and lifespan, it’s important to try to understand how we age and then to propose testable hypotheses on the mechanisms of aging. Historically, one way to do this was to do studies on animals. As described in my previous article on how dietary antioxidants really work, the results of studies on animals gave very misleading results3. That is, caloric restriction without starvation has extended the lifespans of baker's yeast (Saccharomyces cerevisiae), the fruit fly (Drosophila melanogaster), mice, rats and dogs. This idea was based on the assumption that restricting the consumption of total calories would lower the total metabolic rate and the production of reactive oxygen and nitrogen species (RONS) as well as free radicals. This led to the free radical theory of aging, in which it was proposed that the accumulation of damage caused by free radicals causes aging and eventually death. That is, the oxidative metabolism of proteins, fats and carbohydrates in the mitochondria in cells produces RONS and free radicals, which can oxidize and damage DNA, lipids and proteins. This can lead to autoimmune diseases and cancer as well as cardiovascular and neurodegenerative diseases. However, as scientists and physicians learned more about human nutrition, they realized that the caloric restriction that worked for other organisms did not work for humans3. So, the free radical theory of aging has been largely discredited.
Some scientists have suggested that the transcriptome, proteome and/or metabolome can be used to predict biological age4. The transcriptome, proteome and/or metabolome are the collection of all the DNA transcripts, proteins and metabolites that are produced by cells in a person. That is, much of our DNA (genes) is transcribed into RNA. The parts that are transcribed into messenger RNA (mRNA) are then translated into proteins. Some of the proteins that are produced are enzymes. They catalyze the biochemical reactions that occur during metabolism. The products of these reactions are metabolites.
There are two sets of gene expression profiles in the blood that have been used to predict age based on the transcriptome4. The first used five transcripts to predict age. This included lower amounts of the proinflammatory biochemicals interleukin-6 (IL-6) and urea (a metabolite that decreases with age) and increased amounts of serum albumin and decreased muscle strength. The second transcriptome predictor was the levels of 1497 different transcripts. The proteome predictor was based on the attachment of sugars to proteins (protein glycosylation). The amount of glycation on the IgG class of antibodies had some predictive value. The metabolome predictor found some lipids and amino acids that were associated with age. However, the lengths of telomeres in white blood cells and the pattern of methylated DNA are better predictors of biological age4.
Telomeres are complexes of repetitive DNA base sequences, RNA and proteins on each end of chromosomes4,5. They protect the DNA that is at the ends of chromosomes from degradation, fusion with neighboring chromosomes, and inadvertent activation of DNA damage responses. They are also able to generate signals that tell the cell that some of its DNA is damaged, so enzymes can repair it5. When the DNA damage is too severe, telomeres can initiate cell senescence or death5. Telomeres shorten every time a cell divides5. Many studies have shown that a short telomere length is a risk factor for cardiovascular diseases, such as heart attacks and stroke4,5.
However, the pattern of methylation in DNA has been shown to be an even better predictor of not just biological age, but also lifespan and healthspan2,6,7.
The aging immune system
As most people age, their immune system tends to weaken8-10. It does not respond to invading antigens as well, is more susceptible to autoimmune diseases and suffers from chronic, low-grade inflammation that is called inflamm-aging10. The declining function of the immune system is called immunosenescence8. It leads to more frequent infections, as well as a higher susceptibility to cancer and autoimmune diseases8. This is partly due to fewer immune cells being produced by the thymus gland10. That is, hematopoietic stem cells (HSCs) in the bone marrow produce cells that migrate to the thymus gland, where they mature into T-cells10. At the same time, the body produces over 100 million T-cell receptors that can bind to the huge variety of invading pathogens (like bacteria and viruses) that people will encounter throughout their lives10. However, as we age, the size of our thymus gland tends to become smaller in a process called thymic involution or atrophy2,11. Critical populations of immune cells become depleted as the T-cell repertoire tends to collapse after the age of 63. This leads to a higher risk of cancer, infectious diseases, autoimmune conditions, chronic, low-grade inflammation, atherosclerosis and death (all-cause mortality). In contrast, people who live 100 years (centenarians) maintain their immune functions2. The changes in the function of immune cells does not happen because of the genes are mutated. Instead, there is a layer of control on top of (or above) genetics. This is called epigenetics. That is, the transcription of genes into messenger RNA (mRNA) can be turned on or off by attaching a methyl group (-CH3) to a cytosine (C) that is next to a guanosine (G). So, the pattern of methylation of DNA may be an important measure of biological age.
Using recombinant HGH (rHGH) to reverse signs of immunosenescence
HGH (also known as somatotropin) stimulates overall growth while increasing the reproduction and regeneration of human cells. The concentration or level of HGH decreases in the elderly. Children who have don’t make enough HGH have abnormally short stature with normal body proportions. Fortunately, HGH can be manufactured using recombinant DNA technology in which DNA from one organism (such as humans) is transferred into another organism (such as bacteria). The bacteria can make relatively large quantities of HGH that can be sold as an FDA-approved drug. This form of rHGH is expensive and available only in limited quantities. However, many physicians do prescribe it for their elderly patients to improve their strength and stamina. Some competitive athletes also like to use it to improve performance. However, the long-term effects of rHGH have not been tested. Unfortunately, rHGH can increase the level of insulin in the blood to dangerously high levels2. So, it’s not advisable to take rHGH without a prescription or without having regular physicals that include measuring blood glucose. However, there is a dietary supplement, DHEA, that limits the diabetogenic effects of rHGH2.
DHEA - the mother of all hormones
DHEA and its sulfated metabolite, DHEA sulfate (DHEAS) are hormones that are produced in the adrenal glands (located on top of the kidneys), the brain, gonads, adipose tissue and skin12. It has been marketed as the ‘Mother of All Hormones’ due to its ability to be converted into estrogen, testosterone, and progesterone13. The concentration of DHEAS in the blood is about 250 times that of DHEA12. DHEAS is a precursor for about 50% of androgens in adult men, 75% of active estrogens in premenopausal women and almost 100% of active estrogens after menopause14. The concentration of DHEA decreases steadily as most people age. This decrease may be one major reason why many diseases of aging occur. As a result, DHEA and DHEAS have a reputation as anti-aging and able to prevent neurodegenerative diseases, like Alzheimer’s disease14. Moreover, taking DHEA has been shown to improve the effects of insulin in elderly people15. So, its ability to help prevent diabetes is why it was chosen to be included in the clinical trial that appeared to reverse aging2. It should be noted that the DHEA, HGH and metformin used in that study were genuine and pure. The study was done under the auspices of the FDA’s Investigational New Drug (IND) Program (IND 125851) 2, which requires that both current Good Manufacturing Practices (cGMP) and Good Laboratory Practices are followed16. However, the DHEA that is sold as a dietary supplement often is of low quality or produced with poor quality control16. The amount of DHEA can range from 0 – 150% of the dose that is written on the label16.
It should also be noted that both DHEA and HGH are natural substances that can not be patented. Since DHEA can be made cost effectively in the laboratory from a similar substance that is in wild yams, there’s not enough profit in it for major pharmaceutical companies to make it. However, HGH is made through the expensive process of genetic engineering using recombinant DNA. Even though it can’t be patented, the potential for huge growth in demand has made it attractive to several pharmaceutical companies17. That is, the rHGH market was estimated to reach USD 7.1 billion by 202517 even before the recent study showing how it might be able to reverse aging (when taken with DHEA and metformin). Should further clinical trials show that this combination is safe and effective in extending lifespan (reducing mortality), this new drug combination will be made safely and with good quality control (cGMP), as required by law.
Metformin (Glucophage®) may extend lifespan by itself
As described in my previous article in WSI, the standard first line treatment for type-2 diabetes (metformin or Glucophage®) may be able to help people live longer, healthier lives18. It reduces the incidence of cancer and mortality, while helping people retain proper cognitive function. It also favorably influences metabolic and cellular processes that are closely linked to the development of age-related problems. More importantly, it increases the lifespan of not just people who have diabetes, but also in slowing down the aging process. So, there is a clinical trial underway, called Metformin in Longevity Study (MILES) and another that is being planned called Targeting Aging with Metformin, or TAME. These studies will look at the effects of metformin alone on longevity18. In the meantime, it appears that giving people HGH and DHEA together with metformin may be effective in reversing aging.
Of course, aging can be reversed – the immortal jellyfish
Whether or not aging can ever be reversed in humans is still an unanswered question. However, there are some species of animals in the phylum Cnidaria that can and do reverse aging in themselves19,20. At least two of them have been called immortal jellyfish. Their scientific names are Turritopsis nutricula and Turritopsis dohrnii. They can revert to the sexually immature (polyp) stage after becoming sexually mature21,22. They can make many copies of themselves – as immature polyps. They can all reverse their life cycle and avoid death, unless they are eaten by predators. Species in the genus Turritopsis are being studied in more detail to learn how they reverse the aging process22.
In conclusion, a recent small clinical trial showed that a combination of rHGH, DHEA and metformin may be able to reverse aging2. This study used the best available method to measure aging – the pattern of methylation of cytosines next to a guanosine in DNA. It has been shown to be an even better predictor of not just biological age, but also lifespan and healthspan2,6,7.
In my next article, I will continue the theme that science is a process of continuous improvement. I will describe how this happens in new drug development. Some prescription drugs were approved by the US FDA and other governments’ organizations without knowing how they work. Some were approved for treating one disease, but later found to be effective in treating other diseases. Some were approved and have been safe and effective for many years without knowing how they work. Then, a recent study used CRISPR to show that some cancer drugs currently being tested were designed using false therapeutic targets. Still, if the anti-cancer drugs cure cancer and save lives, does it really matter if they were designed based on a faulty hypothesis?
We are a strange species
We are a strange species indeed23! Intelligence is one of our greatest strengths and weaknesses. It tempts us to try to reverse aging, while we continue to live on the verge of self-inflicted extinction from nuclear war and global climate change24. If we don’t end our addiction to beef, greenhouse gases and violence, there will be no civilization to support or feed the people who may be able to reverse aging.
1 Smith, R.E. Historical Differences in Dietary Guidelines. Continuously Improving Dietary Guidelines. Wall Street International, 24 October 2019.
2 Fahy, G.M. et al. Reversal of Epigenetic Aging and Immunosenescent Trends in Humans. Aging Cell, Article e13028, published online, 2019, doi.org/10/1111/acel.13028
3 Smith, R.E. How Dietary Antioxidants Really Work. Wall Street International, 24 July 2018.
4 Jylӓvӓ, J. et al. Biological Age Predictors. EBioMedicine, Volume 21, pp. 29-36, 2017.
5 Fasching, C.L. Telomere Length Measurement as a Clinical Biomarker of Aging and Disease. Critical Reviews in Clinical Laboratory Sciences, Volume 55, pp. 443-465, 2018.
6 Horvath, S. and Raj, K. DNA Methylation-Based Biomarkers and the Epigenetic Clock Theory of Aging. Nature Reviews Genetics, Volume 19, pp. 371-384.
7 Lu, A.T. DNA Methylation GrimAge Strongly Predicts Lifespan and Healthspan. Aging, Volume 11, pp. 303-326.
8 Pawelec, G. Age and Immunity: What Is “Immunosenescence”? Experimental Gerontology, Volume 105, pp. 4-9. 2018.
9 Fulop, T. et al. Immunosenescence and Inflamm-Aging as Two Sides of the Same Coin: Friends or Foes? Frontiers in Immunology, Volume 8, Article 1960, 2018.
10 Stahl, E.C. and Brown, B.N. Cell Therapy Strategies to Combat Immunosenescence. Organogenesis, Volume 11, pp. 159-172, 2015.
11 Thomas, R. and Su, D-M. Age-Related Thymic Atrophy: Mechanisms and Outcomes [Online First], IntechOpen, 2019. DOI: 10.5772/intechopen.86412.
12El-Sakka, A.I. Dehydroepiandrosterone and Erectile Function: A Review. The World Journal of Men’s Health, Volume 36, pp. 183-191, 2018.
13 Maturo, M. DHEA – The Mother of All Hormones. Naturo Medical, 2017.
14 Quinn, T.A. et al. Dehydroepiandrosterone (DHEA) and DHEA Sulfate: Roles in Brain Function and Disease. Chapter 3 in Sex Hormones in Neurodegenerative Processes and Diseases, Drevensec, G., ed. InTech Open, London, 2018.
15 Weiss, E.P. et al. Dehydroepiandrosterone (DHEA) Replacement Decreases Insulin Resistance and Lowers Inflammatory Cytokines in Aging Humans. Aging, Volume 3, pp. 533-542, 2011.
16 Rutkowski, K. et al. Dehydroepiandrosterone (DHEA): Hypes and Hopes. Drugs, Volume 74, pp. 1195-1207.
17 Ciston PR Newswire. Human Growth Hormone (hGH) market, 2015 – Key Players are Pfizer, Merck & Co. Eli Lilly and Company, Genetech, Novo Nordisk, Sandoz Interntional, Ferring and Ipsen. 2018.
18 Smith, R.E. Metformin (Glucophage) May Extend Lifespan. Wall Street International, 24 August, 2018.
19 Hasegawa, Y. et al. De Novo Assembly of the Transcriptome of Turritopsis, a Jellyfish that Repeatably Rejuvenates. Zoological Science, Volume 33, pp. 366-371.
20 Piraino, S. et al. Reverse Development in Cnidaria. Canadian Journal of Zoology, Volume 82, pp. 1748-1754.
21 Ma, H. and Yang, Y. Turritopsis nutricula. Nature Science, 2010, Volume 8, pp. 15-20.
22 Matsumoto, Y. et al. Transcriptome Characterization of Reverse Development in Turritopsis dohrnii (Hydrozoa, Cnidaria). G3: Genes, Genomes, Genetics, Early online October 16, 2019.
23 Kaschak, E. Life and Death. We Are a Strange Species. Wall Street International, 18 June, 2018.
24 Burrowes, R.J. Human Violence. Pervasive, multi-dimensional and extinction-threatening. Wall Street International, 8 November, 2019.