While Covid-19 vaccines have dominated headlines, other important vaccines have been developed. They target malaria, respiratory syncytial virus, cystic fibrosis, obesity, several metabolic diseases (including diabetes), heart failure, endometriosis, lupus, inflammatory bowel disease, atopic dermatitis, and many types of cancer1,2. There have even been vaccines that reversed aging in mice3-6. They removed dangerous cells that had become senescent instead of dying. Good health depends, in part, on the continuous breakdown and regeneration of cells, organelles, proteins and other parts of cells.

We are complex, self-regenerating, autopoietic organisms, whose bodies are ecosystems living in larger ecosystems. Life is sustained by a network of production processes, in which the function of almost every component is to participate in the production or transformation of itself and the other components in the network7,8. A systems view of life and health encourages one to look for interactions within systems, instead of reducing life to a machine that consists of separate components. For example, the nervous system, immune system and endocrine system should not be thought of as independent systems. Instead, they form a neuroendocrine system. It includes not only the organs that were traditionally considered to be part of the endocrine system (such as the pancreas), but also, bones, adipose tissue, muscles, kidneys and the lymphatic system.

The importance of stem cells in modern medicine was described recently in this journal9. Stem cells replenish dead cells. Stem cells repair and maintain muscles, bones and our neuroendocrine immune system. Healthy mitochondria, ribosomes and other organelles are very important in regulating the vital functions of all cells. Key proteins must be broken down and re-made when needed. Just as the entire body must maintain overall homeostasis, cells inside it must maintain balanced protein homeostasis (proteostasis) network10. Proteins are made on an organelle called a ribosome. Proteins must fold into their proper three-dimensional structures to support health. Misfolded proteins can form plaques that lead to oxidative damage and diseases such as Alzheimer’s disease. Properly folded proteins that control cellular metabolism must be degraded when not needed. Both misfolded and normal proteins can be degraded by an organelle called a proteasome. The energy needed for these and other essential cellular processes is provided by mitochondria. Together, they maintain healthy proteostasis. The loss of proteostasis and stem cell exhaustion are two of the hallmarks of aging10. Stem cell homeostasis is maintained by controlling the translational of RNA into proteins on ribosomes, and breaking down proteins on proteosomes when needed. There is also a layer of control above the DNA (genome), called the epigenome. It can turn DNA transcription into RNA either off or on by attaching or removing markers, such as methyl groups. There is also an epitranscriptome that modifies proteins that have been transcribed. For example, the attachment and removal of phosphate groups on proteins can activate or inactivate them. The epitranscriptome, translational control, and protein degradation work together to regulate proteomes, which help control stem cell identity and function11. Aging is linked to a decreased ability to regenerate tissues, and an increased incidence of degenerative diseases12. As a result, stem cell function declines in many tissues during aging. This is especially true in blood and the neuroendocrine immune system.

At the same time, stem cell therapy has great potential in regenerative medicine13,14. Stem cells can be totipotent, pluripotent, multipotent or unipotent. Totipotent cells in a zygote can differentiate into all types of cells. Pluripotent stem cells (PSCs) can differentiate into almost any type of cell. They can be embryonic stem cells (ESCs) or cells from the germ layers (mesoderm, ectoderm and endoderm). Multipotent stem cells can only differentiate into closely related cells. For example, hematopoietic stem cells can become red blood cells, white blood cells and platelets. Unipotent muscle stem cells can only differentiate into muscle cells. Mesenchymal stem cells (MSCs) are tissue-specific stem cells that are used to repair damaged tissue and are useful in regenerative medicine. MSCs can generate bone, cartilage and other types of tissue. Using MSCs does not cause ethical problems compared to ESCs, and are less tumorigenic than PSCs. Extracellular vesicles from stem cells may also be useful in regenerative medicine14,15.

Endogenous stem cells are being used to repair and regenerate tissues, including human lens tissue in eyes, which can be damaged by cataracts13. They are the leading cause of blindness worldwide. Until recently, the only treatment for cataracts was to extract the cataractous lens and implant an artificial intraocular lens. However, this procedure can cause complications. So, researchers designed a surgical method to remove cataracts and preserve the patient’s endogenous stem cells. They regenerated functional lenses in rabbits and macaques, as well as in human infants.

Another approach is to protect one’s stem cells from oxidative damage caused by senescent cells that should have died when they stopped dividing, but didn’t. There is a limit to how many times that many human cells can divide. In 1961, Leonard Hayflick and Paul Moorhead discovered this limit by studying diploid fibroblast cell lines, which failed to divide after 40–60 cell divisions16. After about 50 cell divisions, programmed cell death should occur. However, some cells can become senescent17. They enter a state of cell cycle arrest in response to damaging stimuli. Senescent cells appear throughout the human lifespan. They can persist and damage tissues due to the many proteins they secrete.

Senescence can be protective at times and harmful at others18. The role of cellular senescence in younger people is to repair and heal wounds. Damaged and senescent cells are removed by the immune system. Senescence is an evolutionary protective strategy. Following non-lethal DNA damage, a cell can become senescent. This prevents it from undergoing malignant transformation. However, as most people age, their immune system is not able to remove all of the senescent cells. Eventually, the accumulation of more senescent cells may help cause several diseases of aging. Despite their growth arrest, senescent cells continue to influence their surrounding environment. They produce and secrete many pro-inflammatory cytokines and signals. This is known as a Senescence-Associated Secretory Phenotype (SASP). It leads to smoldering inflammation, which can cause widespread systemic damage and disease. A balance between oxidation and reduction (redox homeostasis) is needed for maintaining the ability of stem cells to self-renew and differentiate while avoiding senescence19. When redox homeostasis is disturbed by oxidative stress, stem cells can lose some important properties and become senescent or even malignant.

There are some senolytic compounds that can eliminate senescent cells and the damage that they can cause. This includes dasatinib, which has been approved by the FDA and used extensively since 2006. It has a very good safety profile. The natural flavonoids quercetin and fisetin are also senolytics. They are widely available as dietary supplements.

Other researchers are developing vaccines that target and remove senescent cells5,6. Like other vaccines that target specific proteins made by viruses, they target proteins on the surface of senescent cells. One of them slowed the progression of frailty in older mice. The vaccine successfully targeted the senescent cells in fatty tissue and blood vessels. So, it could have a positive impact on other medical conditions linked to aging, such as arterial stiffening and diabetes.

So, stem cell therapy, senolytics and anti-aging vaccines are among the tools that can be used to slow down, prevent and hopefully, someday even reverse aging. As described previously in this journal, 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 a clinical trial20. Further work is being done on this and other approaches.

Notes

1 Smith, R.E. Malaria vaccine is effective in children. How malaria is very different than Covid-19. Meer, 24 May 2021.
2 Smith, R.E. New vaccines for Covid-19, influenza (flu) and syncytial virus, RSV. Meer, 24 Oct. 2022.
3 Suda, M. Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice. Nature Aging, Vol. 1, pp. 1117-1126, 2021.
4 Lear, T.B.; Finkel, T. Senolytic vaccination: a new mandate for cardiovascular health? J. cardiovasc. Aging, Vol. 2, 17. 2022.
5 Nakagami, H.; Yoshida, S.; Morishita, R.; Rakugi, H. CD153 vaccine is a novel senotherapeutic option for removing senescence-associated T cells. J. Hyperten. 2021, 39, e286.
6 Yoshida, S.; Nakagami, H.; Hayashi, H. et al. The CD153 vaccine is a senotherapeutic option for preventing the accumulation of senescent T cells in mice. Nature Communications, Vol. 11, article 2482, 2020.
7 Capra, F and Luisi, P.L. A Systems View of Life: A Unifying Vision. Cambridge University Press, Cambridge, UK, 2014.
8 Luisi, P.L. The quest for wholeness. The systems view and the search for spirituality. Meer, 23 May 2017.
9 Wynne, S. Stem cells. Are they the future of modern science? Meer, 1 Dec., 2022.
10 Chua, B.A. & Signer, R.A.J. Hematopoietic stem cell regulation by the proteostasis network. Current Opinion Hematology, Vol. 27, p. 254–263, 2020.
11 Chua, B.A.; ven der Werf, I.; Janieson, C.; Signer, R.A.J. Post-transcriptional regulation of homeostatic, stressed, and malignant stem cells. Cell Stem Cell 2020, 26, 138-159.
12 Signer, R.A.J.; Morrison, S.J. Mechanisms that regulate stem cell aging and life span. Cell Stem Cell 2013, 12, 152-165.
13 Signer, R.A.J. Lens regeneration using endogenous stem cells with gain of visual function. Nature, 2016, 531, 323–328.
14 Song, B-W. et al. Multiplexed targeting of microRNA in stem cell-derived extracellular vesicles for regenerative medicine. BMB Reports, Vol. 55, p. 65-71, 2022.
15 Jarrige, M. et al. The future of regenerative medicine: cell therapy using pluripotent stem cells and acellular therapies based on extracellular vesicles. Cell, Vol. 10, article 240, 2021.
16 Hayfick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Experimental Cell Research, Vol. 25, pp. 585–621, 1961.
17 Chaib, S.; Tchkonia, T.; Kirkland, J.L. Cellular senescence and senolytics: the path to the clinic. Nature Medicine, Vol. 28, pp. 1556-1568, 2022.
18 Lear, T.B.; Finkel, T. Senolytic vaccination: a new mandate for cardiovascular health? J. cardiovasc. Aging Vol. 2, article 17, 2022.
19 Yuan, H. Role of Nrf2 in cell senescence regulation. Molecular and Cellular Biochemistry, Vol. 476, pp. 247-259, 2021.
20 Smith, R.E. Can aging be reversed? Science is a process of continuous improvement. Meer, 24 Dec. 2019.