Today there are two theories that are the most popular in the longevity community: Strategies for Engineered Negligible Senescence (SENS) that were summed up in Aubrey De Grey’s book Ending Aging published in 2008, and the epigenetic theory of aging based on the article “DNA methylation age of human tissues and cell types” published in the journal Genome Biology by Steve Horvath in 2013.

There has been rapid progress during the last 10–15 years in the understanding of how the organism or cells work and we now have a big mass of new scientific information to find the right approach to defeat aging that were left unnoticed by the longevity community.

According to my observation on the internet, the longevity community prefers the theories that postulate stochastic damage as the main cause of aging over the theories of programmed aging. It is not surprising when most of scientific papers accuse DNA damage, free radicals, and cellular junk as the sources for the gradual deterioration of the body.

Stochastic damage is perceived as an inevitable consequence of normal metabolism due to the imperfection of the maintenance system. It is a very simple idea because all things in the Universe are deteriorated in the course of time. You could not imagine living organisms were some exception from the general sample. But living organisms are in fact an anomaly because even a single cell is an incredibly complex system so we cannot achieve this complexity with all of our technologies. Therefore, we cannot apply a trivial perception of things as an explanation of aging.

It is difficult to oppose the theories of stochastic damage because there are too many appeals to the unknown. It is hypothesized as if damage does not reveal itself until the body stops growth or metabolism causes damage. In this case, it leads to a ridicule conclusion that a decrease in physical activity can prolong a lifespan. It is not a joke because many scientists in the XIX century believed in it.

If aging is programmed what is this program? The proponents of programmed often fail to address this issue and try to convince the people through a distant approach of some evolution purpose or systemic changes in the epigenetic clocks based on the methylation of DNA. First, we should assure the genome does not work as a directive computer program. The expression of genes regulated by myriads of transcription factors and hormones. It is like event-driven programming. Transcription factors and hormones change the expression of genes and it leads to the next events in the cell and organism. So there is something that breaks the organism and causes damage.

So what properties can have this program? This program should be induced after maturation and can be affected by nutrition, stress, and other stimuli. This program should be stable against point mutations due to multiple duplicates. We look at the genome and cannot find it because it is not a normal protein-coding gene but endogenous retroviruses. In the article Endogenous retrovirus-K promoter: a landing strip for inflammatory transcription factors?, it is shown the human endogenous retroviruses K (HERV-K) have multiple regulatory loci for transcription factors and hormone receptors. It is especially important regulatory loci for NF-kB, estrogen, progesterone, androgen and glucocorticoid receptor. These viruses are the most active among other endogenous retroviruses. More details on these viruses — Hidden enemy in our cells.

You can still think it is not enough to convince you. So if aging is caused by DNA damage it should change gene expression. However, the authors in the article “Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing” wrote…

As aging is associated with random damage to DNA (Gensler & Bernstein 1981), we tested the hypothesis that this would result in widespread deregulation of gene expression. Instead, we found that human aging is associated with a small number of focused changes, mainly in individual genes associated with immune cell function.

But there are so many papers where DNA damage and mutations in DNA damage repair system led to accelerated aging? How can DNA damage induce aging? DNA damage is linked to the NF-kB inflammatory signaling pathway through ATM that is activated by DNA double-strand breaks. More details on DNA damage-induced inflammation in “Nuclear initiated NF-κB signaling: NEMO and ATM take center stage”.

Chronic inflammation is accompanied by patterns of cytokines, chemokines, and growth factors called senescence-associated secretory phenotype that is induced by NF-kB according to “Emerging role of NF-κB signaling in the induction of senescence-associated secretory phenotype (SASP)”. Therefore, the aging phenotype is exhibited by the induction of chronic inflammation through NF-kB.

But why DNA damage is increased with age? Because retrotransposons, mostly the L1 (LINE-1) retrotransposons, cause DNA damage during integrations into the genome, because the human LINE-1 retrotransposon creates DNA double-strand breaks. Therefore, retrotransposition is associated with genome instability during chronological aging. The activity of the L1 retrotransposons is affected by methylation controlled by the anti-tumor factor p53. The p53 activity determines the methylation of L1. Moreover, p53 genes function to restrain mobile elements in general. So the high rate of mutations in cancer cells is explained by retrotranspositions. As you can understand, mutations are not the cause of cancer but an adaption to increase the vitality and survival of cancer cells.

The main driver of chronic inflammation is NF-kB that is an antagonist of p53 and the interplay between p53 and NF-kB determines will the cell becomes senescent or cancerous. In the article “p53 and the Carcinogenicity of Chronic Inflammation”, Gudkov and Komarova wrote…

Unfortunately, what appears to have been originally designed by nature for rational and effective prioritization of responses to different types of stresses can produce disastrous outcomes when the mechanism of NF-κB-driven p53 suppression is misused and deregulated — as happens under conditions of chronic inflammation.

p53 and NF-kB are major signaling pathways that conduct stress response in the cell. You can realize the cell becomes senescent or cancerous due to some persistent stress stimulus so the cell cannot overcome this stress. The HERV-K prevents the resolution of chronic inflammation because the HERV-K is activated both by NF-kB and glucocorticoids. Glucocorticoids are vital in the negative feedback loop that switches off NF-kB through the antagonism with it. This mechanism was described in my article “How endogenous retroviruses make us old?”.

You may perceive chronic inflammation as one of the multiple hallmarks of aging. In fact, chronic inflammation is a very complex process… it is the crossroad of aging, cancer, and autoimmune diseases. There are mechanical explanations of multiple diseases and age-associated pathological processes through the action of inflammatory pathways.

Cellular junk and Alzheimer disease:

Insulin resistance, obesity, fatigue, and even quality of life:

Heart diseases and other organ diseases:

Reproductive decline due to the inflammation of the hypothalamus:

Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH