On the cause of aging and control of lifespan: heterogeneity leads to inevitable damage accumulation, causing aging; control of damage composition and rate of accumulation define lifespan

Abstract

What the causes of aging are and which factors define lifespan are key questions in the understanding of aging. Here, it is argued that cellular life involves (i) inevitable accumulation of damage resulting from imperfectness and heterogeneity of every cellular process, and (ii) dilution of damage when cells divide. While severe damage is cleared by protective systems, milder damage can only be diluted. This is due to the high cost of accuracy, the greater number of damage forms compared to protective systems, and the constraints on cellular life inherited from the prokaryotic world. This strategy also applies to cancer cells, which are particularly dependent on damage dilution. Imposing restriction on cell division necessarily leads to aging. Interventions that extend lifespan act through metabolic reprogramming, thereby changing both damage composition and the rate of damage accumulation. Thus, heterogeneity leading to myriad mild damage forms represents the cause of aging, whereas the processes that affect the damage landscape and damage accumulation are lifespan regulators.

Fig. 1. Enzyme-generated damage

Enzymes inevitably generate by-products. Consider a pathway of 10 enzymes, each with 99.9% accuracy, which would represent a very impressive specificity. However, when only 100 molecules pass through this pathway, 1 molecule would be lost to numerous by-products resulting from 0.1% inaccuracy in each step. Significant flux through this pathway can easily make by-products more abundant than the product itself.

Fig. 2. Damage dilution

Cells deal with the accumulation of mild damage (shown in red) by diluting it during cell division.

Fig. 3. Control of lifespan by regulating rate and pattern of damage accumulation

Interventions that extend lifespan both change the landscape of damage in cells (i.e. different damage is accumulated) and decrease the rate of its accumulation.