The viral theory of aging
Aging is one of the greatest mysteries of life and the search for “eternal youth” has persisted since the very beginning of humankind
Aging is perceived as a consequence of natural unavoidable processes in the organism like mutations or radical oxygen species but the suppression of these processes does not alleviate aging. Moreover, it decreases the capability of the organism. So, in my opinion, aging arises not due to molecular damage and therefore bodies are not worn out as human-made tools, materials or devices. In living organisms, there are constant processes of growing and regenerating, and the logic that is appropriate for cars and clothes is not appropriate for living creatures. Here, I’d like to describe my novel theory that some types of genomic parasites (endogenous retroviruses) are involved in chronic inflammation that causes the global-scale changes in the organism that leads to senescent phenotype and death.
The mechanism of aging is very tricky and stable for various therapies. Now we can only slightly delay aging by a healthy lifestyle. I supposed that to solve the problem of aging, we need to measure aging quantitatively. In other words, we should find accurate markers of aging so we can investigate effective methods to reduce aging processes. In 2013, bio-statistician Steve Horvath (UCLA) published his article where he described his method to get accurate markers representing chronological age based on the methylation of DNA. More strikingly, these markers exhibited extraordinary accuracy and correlation with chronological age with more than 0.95 correlation. Almost full correlation with chronological age prompted the emergence of an idea that the epigenetic clock shows the true biological age. Therefore, if the epigenetic clock goes faster or slower, we can reveal which factors are involved in aging. Accelerated aging, almost in any examples, shows anomalously increased chronic inflammation in the tissues of patients with Down syndrome, HIV infection, Werner syndrome, Alzheimer and Parkinson diseases, etc. However, the Horvath’s clock doesn’t show accelerated aging in progeria patients when aging emerges since early childhood but later more advanced clocks indeed show accelerated aging. Moreover, in the article “Motif module map reveals enforcement of aging by continual NF-κB activity”, it was shown the transcription factor NF-κB is up-regulated with most human and mouse tissues.
The NF-κB protein complex is the main conductor of inflammation response induced as a reaction to pathogens or tissue damage. Also, in the article “Methylomic predictors demonstrate the role of NF-κB in old-age mortality and are unrelated to the aging-associated epigenetic drift”, mortality-associated epigenetic markers clustered around the transcription factor NF-κB. Although mortality-associated markers are not overlapped with age-associated markers, the phenomenon of accelerated aging is correlated with increased inflammation. Also, the Horvath’s clock represents the entire individual development so the patterns of maturation and patterns of age-associated degeneration are mixed up together in his epigenetic clock.
The pluripotency factors (Oct4, Sox2, c-Myc, and Klf4) also called the Yamanaka factors, who found with these factors the way to reprogram somatic cells into stem cells, are able to reverse the epigenetic clock to nearly zero years. Interestingly, if partially reprogram somatic cells with the pluripotency factors, mice are rejuvenated. This confirms that chronic inflammation causes aging but not mutations or reactive oxygen species. The reversal of the epigenetic clock with pluripotency factors leads to decreased chronic inflammation. Although, the pluripotency factors may induce tumors so this therapy has a substantial risk for patients. One of the most dangerous pluripotency factors is c-Myc. This effect may be explained by a fact that binding sites of c-Myc are located in the regulatory sequences of endogenous retroviruses so c-Myc can activate these dangerous genetic elements in the genome.
Endogenous retroviruses are ancient invaders to our genome, mostly dated to 30–40 million years ago. The majority of endogenous retroviruses are inactive but several families of human endogenous retroviruses are still able to produce viral particles though now can’t infect again. These families are HERV-H, -W, and -K. These viruses are also involved in normal processes as HERV-H supports stem-like phenotype and cell proliferation, and HERV-W protects the embryo from the maternal immunity, but HERV-K perhaps may have mostly a detrimental effect for the organism. HERV-K and HERV-W are implicated in cancer and both have regulatory sequences have binding sites for NF-κB. So chronic inflammation induces the activity of endogenous retroviruses. This point is confirmed by the article “NF-κB and IRF1 Induce Endogenous Retrovirus K Expression via Interferon-Stimulated Response Elements in Its 5' Long Terminal Repeat”
The cause of chronic inflammation in aging is believed as unknown and many scientists make a bunch of hypotheses as if everything causes chronic inflammation. Another virus HERV-W, in an article “The Envelope Protein of a Human Endogenous Retrovirus-W Family Activates Innate Immunity through CD14/TLR4 and Promotes Th1-Like Responses”, induces innate immune response and inflammation. This is accompanied by pro-inflammatory cytokines IL-1beta, IL-6, TNF-alpha that are typical in age-associated inflammation.
Similar conditions are observed for cancer and autoimmune diseases where endogenous retroviruses are suspected as the culprit of inflammation. The difficulty to treat endogenous retroviruses is due to a fact they are already a part of the genome and there is a necessity for genetic engineering to counter these viruses.
HERV-K has also binding sites for sex hormones. So the endocrine system can awake these viruses during maturation but chronic inflammation is not induced immediately in the young organism. This contradiction is explained by the mutual antagonism of sex hormones and inflammation pathways. Because sex hormones induce endogenous retroviruses and high concentration of viral particles eventually leads to chronic inflammation and then to the decrease sex of hormone production. This model is confirmed by dynamics of endogenous retroviruses in a research “Transcriptional Activity of Human Endogenous Retroviruses in Human Peripheral Blood Mononuclear Cells”
During maturation, HERV-K activity surges from 0.43 to 1.8 and slightly decreased to 1.48. Since the age of 40, HERV-K activity is rising. HERV-W rushes from 0.32 for the aged 18–38 to 10.49 for the aged 40–59. Therefore, HERV-K activity leads to the activation of HERV-W. Both HERV-K and HERV-W may be implicated in aging processes but the activity of individual viruses does not show any significant correlation with age but shows correlation within clusters. Presumably, age-associated viruses are located in certain domains of the genome. The most probable candidate is lamina-associated domains (LADs) located on the most peripheral parts of the nucleus. The lamina complexes anchor lamina-associated domains and suppress their expression. During aging, lamina remodels and LADs detach from it and all genetic elements in LADs can be expressed. Among progeria patients, due to defects of the lamina, LADs are not appropriately suppressed and chronic inflammation occurs prematurely.
This viral program is very stable because the viruses act in a group consisting of multiple copies of viruses and it is unlikely that random mutations can damage all of them. Other parts of this program: the inflammation pathways or epigenetic maintenance enzymes are so vital, so mutations of these pathways are often lethal for the organism since the zygote. There are more difficulties because viruses are engaged in different roles in the organism having a beneficial or neutral effect. So it will be oversimplified to shut down all viruses to eliminate the deleterious effect of viruses. Modern achievements in molecular biology, bioinformatics, and gene engineering can provide tools to locate and clear the viruses that have with negative effect in the organism. This consequence implies more broad perspectives — a cure for cancer and autoimmune diseases.
