Discussing the DNA Damage Hallmark of Aging at Long Long Life

The Long Long Life team will be putting together a set of videos in the months ahead, one for each of the Hallmarks of Aging. The first to be published covers the hallmark of DNA damage, stochastic mutational change to nuclear DNA that is widely thought to make a meaningful contribution to the dysregulation of cell behavior in aging. This is evidently the case for cancer risk, as cancer is caused by mutations that enable rampant, unregulated growth, but may only be important otherwise when mutations occur in stem cells or progenitor cells that are able to propagate the mutations widely in tissues.

The Hallmarks of Aging is a list of common processes and outcomes found in aging, and considered by a sizable fraction of the research community to cause aging. While the hallmarks overlap with the list of forms of cell and tissue damage described in the earlier Strategies for Engineered Negligible Senescence (SENS), a view of aging as accumulated molecular damage, the two differ in that some of the hallmarks are clearly not fundamental causes of aging in the SENS view. They are some way downstream from the forms of molecular damage that would be considered true causes of aging. For example, the hallmarks include loss of proteostasis and dysregulation of nutrient sensing. Both of these are managed by collections of cell behaviors and states; we must ask what causes those behaviors and states to change, and the answer must be some form of underlying damage.

[Video] The 9 Hallmarks of Aging, episode 1, DNA damage

The first cause of aging that we will address are the damage to our DNA over time. DNA is the medium of information that makes us who we are, the manufacturing program of our body. This information is made up of genes and all genes are grouped together under the name "genome". All this information must be transmitted from one cell to another when they divide to generate daughter cells. And for that, it is necessary to replicate the DNA integrally at each cellular division.

Unfortunately, even this very powerful replication system is not without errors. It has been noted that DNA errors accumulate in life, as many factors influence the stability of the genome. These factors are varied and can be external, such as smoking, sunlight, food ... but also internal, such as replication errors: when your body has to copy the information contained in your DNA, it makes mistakes. These errors can either be repaired, cause cell death, or, and this is the problem, be transmitted to daughter cells.

Fortunately, we have repair systems. Some genes build proteins to repair replication errors, but sometimes the replication errors affect the genes that make these repair systems and, through a snowball effect, there is an exponential growth of problems within the cell. In mice and humans, it has been shown that there is a causal link between DNA damage accumulation and aging. In fact, when the cells in our body divide a large number of times and are carriers of genetic mutations, this causes a dysfunction of the cell that can cause problems at the level of the organ concerned.

Interestingly, it has been shown that during aging, repair systems (such as the PARP protein) become much more abundant in cells, suggesting that our body is aware of the deregulations that come with age and tries to take the necessary steps to fight them. The activity of these repair systems is however dependent on co-enzymes, small molecules that allow them to function. These are essential fuels for our cells whose concentration and recycling decreases with age. Among them, NAD+ is often mentioned, because it is essential to repair mechanisms, but also to mitochondrial health. When these molecules eventually run out, our repair systems no longer work well, leading to serious disruptions, not only in replication but also in other mechanisms, up to and including cell death.

Supplementing with NAD+ may be a good idea to boost our repair systems but it is also possible that cell suicide linked to NAD+ depletion is a protection of the body against cells that have become genetically diseased and that it would be preferable to eliminate. Researchers have used mice, which have been treated to keep a constant level of NAD+ throughout their lives. And not only the treated mice lived healthier lives but they also lived longer than the untreated mice. This shows that, in mice in any case, upregulating NAD+ seems to be a good idea to fight against aging. In humans, as usual, this remains to be proven.

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