As described in previous articles in this journal, there are ways to slow down human aging and lead a longer, healthy life 1-6. Scientists have been able to reverse aging in lab mice 7,8. One organism, Turritopsis dohrnii (T. dohrnii) is even able to rejuvenate repeatedly after its medusae reproduce, so some call it the immortal jellyfish9. It was originally mistakenly identified as Turritopsis nutrricula10. Recently researchers analyzed and compared the genomes and transcriptomes of T. dohrnii and the non immortal Turritopsis rubra. That is, they determined the DNA sequences (their genomes) and discovered which types of RNA and proteins were produced from the transcription of the genomes. They identified variants and expansions of genes associated with DNA replication and repair, telomere maintenance, oxidation-reduction (redox) environment, stem cell population, and intercellular communication9.
The importance of stem cells has been discussed before in this journal5,6. In a healthy tissue and human body, they are masters of autopoiesis, or self-making. That is, all living systems continuously break down components within a boundary, such as a cell membrane, the epithelial layer of tissues, or a person’s skin. For tissue to remain healthy, old and damaged cells must die and be replaced. Tissue stem cells produce replacement cells. When a stem cell divides by mitosis, it produces one copy of itself and another copy which is differentiated into the specialized cell being replaced. An important example of this is blood cell production and differentiation into specialized cells. Pluripotent stem cells can differentiate into many types of cells11. As one ages, one’s ability to regenerate tissues decreases when stem cells are damaged. This can occur due to DNA damage, shorter telomeres, dysfunctional energy production and the production of tumor suppressors9,11,12.
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 immune systems in people who participated in a clinical trial2,12. Metformin activates a key enzyme that is depleted in the elderly. It is called adenosine monophosphate-activated kinase, or AMPK13. Metformin reduces the incidence of cancer and mortality while helping people retain proper cognitive function2. 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 process2.
However, some cells become senescent and don’t die. Instead, they cause damage by producing inflammatory cytokines and chemokines, immune modulators, growth factors and proteases6. They can do a lot of damage, they can cause chronic inflammation, and they can encourage nearby healthy cells to also become senescent. And in an effort to survive, senescent cells can even cannibalize surrounding cells to utilize their resources. Senescent cells don't accumulate in most young, healthy people because they are removed by their immune system. However, as most people age, their immune system becomes less effective. As a result, more senescent cells evade destruction and begin to accumulate. There are some dietary antioxidants in fruits and vegetables which act as senolytics when they help kill senescent cells. Examples include quercetin, fisetin and piperlongumine6. The dietary antioxidant resveratrol supports the function of healthy mitochondria and energy production. In addition, consuming dietary fiber and eating little or no meat stimulates the growth of healthy bacteria in the gut. This supports the immune system and leads to healthy aging14.
As we age, the amount of a key substance needed to maintain healthy energy function becomes depleted. It is call NAD+, or nicotinamide adenine dinucleotide15. It is quickly digested and broken down when consumed. Instead, a metabolic precursor called NAD-riboside can be taken to increase the amount of NAD+ in the blood and in key cells. It promotes the production and proliferation of brain cells while improving cognitive function and inhibiting the growth of cancer cells15.
The immune system in many older people 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-aging2,16. The declining function of the immune system is called immunosenescence17. 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 gland. That is, hematopoietic stem cells (HSCs) in the bone marrow produce cells that migrate to the thymus gland, where they mature into T-cells. 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 lives.
However, as we age, the size of our thymus gland tends to become smaller in a process called thymic involution or atrophy2,18. 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 functions. The changes in the function of immune cells does not happen because 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.
Epigenetics was used to reverse age-induced morphological decline of retinal pigment epithelial cells. They reversed the biological age of retinal ganglion cells19. Previous research laid the foundation for this. A Japanese biomedical researcher, Dr. Shinya Yamanaka, had already converted human adult skin cells into pluripotent embryonic stem cells17. They were capable of developing into any cell in the body. He used four protein transcription factors (Oct3/4, Sox2, Klf4 and c-Myc) that became known as Yamanaka factors. He was awarded the Nobel Prize for this discovery. However, the cells lose their identity and are not suited for regenerating tissues. This was followed by subsequent work. Genes coding for three of the four factors were added to a harmless virus. After injecting the virus into the eye, the genes were switched on by feeding the mouse an antibiotic. Damaged neurons in the eyes rejuvenated, growing new axons that extend from the eye into the brain. Since that study, David Sinclair’s lab at Harvard Medical School has reversed aging in the muscles and brains of mice. He is now working on rejuvenating a mouse's entire body7.
However, we are not mice. There are things we can do to increase or decrease our stress. We can spend quality time with loved ones, meditate, pray and exercise. These things reduce stress and help to extend one’s lifespan. More importantly, they increase our health span, or the number of decades and years that we are healthy and not just surviving with pain, depression, loneliness and chronic diseases.
1 Smith, R.E. Metformin (glucophage) may extend lifespan. Slowing down the aging process. Meer, Aug. 24, 2018.
2 Smith, R.E. Can aging be reversed? Science is a process of continuous improvement. Meer, Dec. 24, 2019.
3 Freire, T. Vitamin D and antiaging. Unravelling of hidden secrets. Meer, 29 July, 2021.
4 Freire, T. Metformin and aging. Metformin currently shows promising effects against factors that promote aging. Meer, 29 Nov., 2021.
5 Freire, T. Telomerase and senescent cells in antiaging. One of the world’s greatest discoveries in the science of human evolution. Meer, 29 May, 2022.
6 Freire, T. Senolytics in antiaging. They say nothing lasts forever; we'll have to prove them wrong. Meer, 29 June, 2022.
7 LaMotte, S. The 'Benjamin Button' effect: Scientists can reverse aging in mice. The goal is to do the same for humans, CNN, 15 July 15, 2022.
8 Karg, M. et al. In vivo epigenetic reprogramming reverses the age-induced morphological decline of retinal pigment epithelial cells. ARVO Annual Meeting Abstract, 2021.
9 Pascual-Tomer, M. et al. Comparative genomics of mortal and immortal cnidarians unveils novel keys behind rejuvenation. Proceedings of the National Academy of Science, PNAS, Vol. 119, article e2118763119, 2022.
10 Ma, H. and Yang, Y. Turritopsis nutricula. Nature Science, 2010, Volume 8, pp. 15-20.
11 Signer, R.A.J. & Morrison, S.J. Mechanisms that regulate stem cell aging and life span. Cell Stem Cell, Vol. 12, 2013.
12 Fahy, G.M. et al. Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell, Article e13028, 2019.
13 Amorim, J.A. et al. Mitochondrial and metabolic dysfunction in aging and age-related diseases. Nature Reviews Endocrinology, Vol. 18, pp. 243-258. 2022.
14 Smith, R.E. Dietary fiber, the gut microbiome and health. There is an undeniable link between the brain, the gut and the immune system. Meer, April 24, 2020.
15 Huang, X. et al. NAD+ modulates the proliferation and differentiation of adult neural stem/progenitor cells via Akt signaling pathway. Cells, Vol. 11, article 1283, 2022.
16 Stahl, E.C. and Brown, B.N. Cell therapy strategies to combat immunosenescence. Organogenesis, Volume 11, pp. 159-172, 2015.
17 Pawelec, G. Age and immunity: What is “Immunosenescence”?. Experimental Gerontology, Volume 105, pp. 4-9. 2018.
18 Thomas, R. and Su, D-M. Age-Related Thymic Atrophy: Mechanisms and Outcomes, Online First, IntechOpen, 2019.
19 Karg, M. et al. In vivo epigenetic reprogramming reverses the age-induced morphological decline of retinal pigment epithelial cells. ARVO Annual Meeting Abstract, 2021.