During the last century in medicine, much progress was made in controlling infectious diseases. The associated human mortality has considerably gone down and nowadays most mortality is attributed to aging-related diseases (ARDs) that include heart disease, cerebrovascular disease, Alzheimer’s disease, and, as a major player, cancer.
The current generally accepted theory for ARDs is the Somatic Mutation Theory (SMT), with many pertinent somatic mutations being linked to the lifestyle of the individual. Mutations, and more generally, genomes are extensively investigated. Epigenetic studies can be considered a variation of this approach.
The practical use of the genome-based investigations in new therapies has however been limited, as is especially well known for cancer. The numerous adverse genes found in Genome-Wide Association Studies seem to make general cures implausible and plausibly argue for approaches based on individual medicine, which, if feasible therapeutically, would be quite involved and expensive.
Several observations are hard to combine with the SMT. Differences in maximal lifetimes between animals suggest that aging is under genomic control. Moreover, ARDs show many mutual similarities, in particular, a key initiating role for inflammation, not only after infection but also after distortion of homeostasis. For cancer, the immune system can both stimulate and inhibit cancer. Moreover, aging and cancer are ubiquitous in most organs and, on a higher level, in most species as well, whereas one expects that during evolution selection would have removed aging and cancer.
These and other discrepancies and contradictions with the SMT were motivation to search for a new explanation for aging and cancer, and to formulate the Unified Cancer & Aging Adaptation (UCAA), presented in two studies: Cancer is an adaptation that selects in animals against energy dissipation (2017) and Aging is an adaptation that selects in animals against disruption of homeostasis (2018), both published in Medical Hypotheses. In the UCAA, aging and cancer, although obviously detrimental to the individual organism, give a benefit to the species.
In a nutshell, the idea is that the adaptation actively removes deleterious mutations such as continuously generated by H.J. Muller’s ratchet. Their negative physiological effects are during the life cycle detected by the Adaptation and are followed by the initiation of aging and cancer, which remain dormant until reproduction. Thereafter, the adaptation ends dormancy: the stronger the initiation signal, the sooner. The next step involves the self-actuated death in old age proposed by Skulachev and termed “phenoptosis.” As a result of this parental death, assumed to be accelerated proportional to the initiating signal, the offspring receives less parental care and its chances to reach adulthood are diminished. The overall effect over many generations of the Adaptation is a purifying selection against deleterious genes.
Image courtesy Anthonie Muller
In the case of cancer, the progress would involve a cascade of repeated amplification over multiple scales of enhanced energy dissipation, at first causing intracellular heating, and followed by heat shock, the Warburg effect, the cytokine IL-6, metastasis, tumors, hypermetabolism, cachexia, parental death, and enhanced chance of offspring death.
Extreme longevity (age >> 80), such as occurs in some populations, is explained as a result of mutation of the genes needed for the adaptation. It is predicted that in these populations, deleterious mutations are not so quickly removed as in populations in which aging and cancer are active.
The new theory unifies many observations and resolves many contradictions. If found to be correct, the theory should result in better therapies for aging and cancer.
The findings are discussed in further detail in the articles recently published in Medical Hypotheses, Cancer is an adaptation that selects in animals against energy dissipation and Aging is an adaptation that selects in animals against disruption of homeostasis, authored by Anthonie W.J. Muller from the Synthetic Systems Biology – Nuclear Organization Group of the Swammerdam Institute for Life Sciences, University of Amsterdam.
References:
- Anthonie W.J. Muller, Cancer is an adaptation that selects in animals against disruption of homeostasis. Medical Hypothesis 104 (2017) 104-115. https://linkinghub.elsevier.com/retrieve/pii/S0306987716310246
- Anthonie W.J. Muller, Aging is an adaptation that selects in animals against disruption of homeostasis. Medical Hypothesis 119 (2018) 68-78. https://linkinghub.elsevier.com/retrieve/pii/S0306987718306169