Hidden enemy in our cells
Most people do not know about viruses that are always with us since birth. If you catch flu, usually it does not affect your descendants. However, it was not that case in past times.
Endogenous retroviruses
During the long constant evolution of our ancestors, the human genome of our precursors was persistently bombarded by viruses. Waves of their invasions left multiple copies of inactive viruses that aimed to integrate themselves into the genome. Endogenous retroviruses are viruses that are successfully integrated into the genome. The prefix “retro-” means these viruses use reverse transcriptase to insert their DNA into ours because this enzyme transcribes from RNA to DNA instead of the regular process of transcription from DNA to RNA. Retroviruses use this mechanism because they store genetic information in RNA — a very compact molecule. Because of it, retroviruses are very tiny and have only 3 genes.
Endogenous retroviruses in diseases
The majority of the endogenous retroviruses are inactive due to the activity of our anti-viral defense, but the human endogenous retroviruses K (HERV-K) are relatively young and are integrated into the human genome around 2–3 million years ago. These viruses are similar to MMTV (mouse mammary tumor viruses) that belong to beta oncoviruses. Indeed, HERV-K are very active in cancer such as in breast cancer, melanoma, lymphoma, ovarian cancer, teratocarcinoma, germ cell tumors, prostate cancer), but more interestingly also in autoimmune diseases as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), schizophrenia, amyotrophic lateral sclerosis (ALS), multiple sclerosis, etc.
Chronic inflammation in diseases and aging
All the mentioned diseases are featured by prolonged persistent chronic inflammation. Chronic inflammation is observed in Parkinson disease, cancer, Werner syndrome, Hutchinson–Gilford progeria syndrome, etc. In the cases of the Werner and Hutchinson-Gilford syndrome, we can observe accelerated aging accompanied by increased chronic inflammation that is typical for normal aging. Also, the organism of long-lived people can slightly decrease chronic inflammation, so longevity is associated with the suppression of chronic inflammation reducing of chronic inflammation led to aging amelioration.
Chronic inflammation is the culprit of aging
Therefore, we can conclude chronic inflammation is the main factor in aging, cancer, and autoimmune diseases. Chronic inflammation is regulated by the NF-kB inflammatory pathway. Epigenetic markers reveal NF-kB as the main factor of mortality at old ages.
The conflict between the programs of proliferation and differentiation
In the organism, there are two parties of signaling pathways: the party of the youth cells and growth, and the party of the adult cells and maturity. Since the organism has grown up, the party of maturity dominates. The p53 signaling pathway promotes cell differentiation when stem cells become functional but lose the ability of cell division. In a case of some stress or damage, the party of growth comes back. The organism has a unified mechanism for stress response and growth through the STAT, NF-kB, and mTOR inflammatory pathway. Due to this fact, cells try to reverse their status to a more stem-like state. However, if p53 is still active it leads to the conflict and antagonism between the two parties of cellular signaling. A cell may proceed two ways: either inflammation wins and the cell becomes cancerous, or p53 wins and the cell becomes senescent. So the balance between NF-kB and p53 determines the fate of a cell that are the main regulators of inflammation and differentiation respectively.
Cellular junk accumulated due to chronic inflammation
The inflammatory pathways prepare the cell to proliferation when it will intensively divide and grow, through suppression of programmed cell death and decreasing autophagy. Autophagy is a mechanism that cells use to rid of cellular junk. By decreasing autophagy, the cell collects enough resources for growth, but if the cell arrested by p53, it is flooded with unused materials.
Damage induced by chronic inflammation
Chronic inflammation promotes hypoxia. During proliferation, cells become more like a unicellular organism. Cells use glycolysis instead of oxidative phosphorylation and it prompts the release of reactive oxygen species (ROS) due to changes in mitochondrial metabolism. ROS act as catalysts for all processes in the cell that are vital in cell growth and division. Moreover, ROS activate the mechanism of accelerated evolution as a response to a stress stimulus. ROS cause demethylation of DNA and activate mobile genetic elements: Non-LTR retrotransposons that are similar to endogenous retroviruses but these can “copy-paste” themselves in the genome. This phenomenon leads to an increased rate of mutations.
DNA damage cannot itself cause aging but it can be detected by the receptors of the DNA damage response (DDR) system: ATM and ATR. Because DNA damage is also a stress stimulus, it also induces inflammation.
Degeneration induced by chronic inflammation
Pro-inflammatory cytokines induce muscle atrophy and osteoporosis when bones become fragile due to calcium depletion. The extracellular matrix (ECM) is remodeled due to the activity of matrix metalloproteinases. More elastic fibers are degraded early and the ECM becomes stiffer. The stiff ECM causes the loss of stem cell niche and their depletion. It reduces regeneration capacity and a decrease in the size of organs. The production of melanocytes is decreased leading to grey hair. Due to the loss of elasticity of the ECM, the skin becomes rigid and has wrinkles.
Stimuli for chronic inflammation
Inflammation is a result of a stress response. Any kind of stress may induce inflammation: radiation, chemicals, UV-light, tobacco smoke, diesel fume, psychological stress, chronic pathogens (viruses and microbes), etc.
How do HERV-K prompt chronic inflammation?
Endogenous retroviruses K (HERV-K, ERVK) break the negative feedback loop between NF-kB and glucocorticoids because glucocorticoids suppress not only NF-kB but also induce HERV-K and the expression of viral particles facilitate NF-kB. HERV-K do not allow glucocorticoids to switch off NF-kB. Several viruses make an aging program not susceptible to point mutations and very stable to external intervention except genetic tools as CRISPR.
HERV-K are activated by inflammation, stress and sex hormones
HERV-K actively interact with the inflammatory pathways and endocrine system due to a great number of binding sites for transcription factors and hormones such as NF-kB, AP-1, STAT, estrogen, progesterone, androgen, and glucocorticoid receptors.
- The methylation of HERV-K is correlated with age that displays the activity of HERV-K.
- HERV-K have regulatory motifs in HERV-K
- HERV-K are induced by steroid hormones and NF-kB
- HERV-K proteins induce the activation of NF-kB
These regulatory motifs help retroviruses to control their expression but during evolution, HERV-K adapted to provide the phenotype of aging and difficult diseases with uncertain etiology such as cancer and autoimmune diseases. HERV-K are similar to MMTV (mouse mammary tumor viruses) classified as beta oncovirus. It is possible beta oncoviruses may be one of the main sources of endogenous retroviruses that determine aging in various organisms.
Suppression of HERV-K
There are no known experiments to suppress HERV-K to alleviate aging. However, the knockdown of HERV-K by RNA interference in cancer cells reduces the growth and size of tumors in spite of the fact RNA interference could only reduce the activity of HERV-K and may not affect the target oncoviruses significantly. If we will be able to turn of the target HERV-K, we can suppress chronic inflammation that will lead to gradual rejuvenation because chronic inflammation damages the organism. The knockout of HERV-K may also eliminate cancer and autoimmune diseases such as amyotrophic lateral sclerosis.
Conclusion
This theory states the four principles:
- Aging, cancer, autoimmune diseases have a common marker — chronic inflammation
- Chronic inflammation causes all degenerative processes and damage in the organism and a cell
- HERV-K prevent chronic inflammation to be turned off
- Genetic tools can rid of the genome from HERV-K rejuvenating the organism to increase radically lifespan.
The mechanism of aging, induced by HERV-K is one of the most amazing and extraordinary processes in nature that limits the lifespans of living organisms. HERV-K use the innate immune response and vital signaling pathways to enforce self-destruction of the organism. The complexity of this mechanism prevented scientists to find the true cause of aging and various diseases with uncertain etiology and to develop effective therapies to treat these diseases.
Now we have the opportunity to get free from aging, cancer, and autoimmune diseases. If we learn how to switch off these viruses, we can enter completely a new world. We need to turn them off!
