The longevity genes that slow aging according to David Sinclair

As someone who wants to proactively slow cellular aging you will be looking for key actions you can implement into your routine to keep you feeling your best. Research has identified many different genes and cellular pathways that are associated with aging, but Professor David Sinclair believes there are three key biological pathways which are vital to regulating our cells and if we can control them, we can slow the aging process.

He refers to these as longevity genes and this article will look at each of them in more detail and how they are linked to NAD+.


mTOR is the cell’s protein sensor

The first longevity gene is mTOR (mammalian target of rapamycin) and it creates a protein complex that is a key component of cellular metabolism. mTOR senses levels of amino acids in your cells. Amino acids are the building blocks of protein, so when you consume a steak or other high protein foods, mTOR becomes activated. mTOR responds by activating other cellular pathways which use this amino acid supply to fuel growth and repair whilst the supply is plentiful.

Whilst mTOR activation is beneficial for building muscle, constant mTOR activation isn’t ideal for longevity.  This has been demonstrated in animal studies which found that when mTOR is inhibited with rapamycin, it extends the lifespan of mice and yeast. Furthermore, in other studies investigating the beneficial effects of calorie restriction mTOR was found to be involved.

The reason mTOR inhibition is beneficial from a longevity perspective, is because it signals to the cell that nutrients are scarce so maintenance and repair pathways are activated to support the cell until nutrients become available again. It’s these maintenance and repair pathways that are critical to aging well.


AMPK is the cell's energy sensor

The second longevity gene is AMPK (AMP activated kinase) which sits at the heart of energy production pathways in your cells. Unlike mTOR, we want to increase AMPK activation. This is because AMPK is activated when cellular energy is low and therefore it increases energy production. It does this by activating pathways which increase the number of mitochondria in your cells and increase NAD+ synthesis, stimulating cellular energy production.

Studies have shown that AMPK activation and NAD+ levels decline with age resulting in less cellular energy, contributing to the feeling of tiredness that we associate with aging. This has generated great interest in finding AMPK activators.

AMPK pathway

One way to naturally activate AMPK is by fasting. Fasting creates cellular stress and switches on longevity pathways including AMPK. This concept of cellular stress being good for your cells is called hormesis and can be achieved by fasting, exercise and cold exposure among others.


Sirtuins control gene expression

Sirtuins are a family of proteins (SIRT1-7) that help to regulate gene expression. There are seven sirtuins in our cells and they help to control epigenetics. As described so well by David Sinclair in his book Lifespan and in one of our previous articles, epigenetics controls which genes are active in the cell. Sirtuins do this by removing ‘acetyl’ markers from the DNA which causes that part of the DNA to become tightly wrapped up and inaccessible to the cell. This inaccessibility means the DNA and the genes can’t be “read”.

We now know that epigenetic information changes as we age, and this drives the ex-differentiation process which causes cell to lose their identity and stop functioning correctly. While sirtuins are only one part of epigenetic regulation, research has shown that sirtuin activation in cells declines with age. This decline has been found to be due to falling levels of NAD+. This is because sirtuins require NAD+ to carry out their function. So when NAD+ levels decline with age, so does sirtuin function.

The activities we are told to do for our health, such as exercising and fasting, have been found to have a beneficial effects in part because they increase cellular NAD+ levels and stimulate sirtuin activation. So keeping NAD+ levels and sirtuin activation as we age should be a part of our routines.


All the longevity pathways are linked

One of the key findings of longevity research is that all these pathways are malleable and can be altered to positively impact aging. In addition to this each of these pathways are connected and communicate with each other. For example, AMPK activation is shown to inhibit mTOR activity, and AMPK activation indirectly activates sirtuins by increasing NAD+ production. 


Professor David Sinclair's Longevity Genes

As with all things in biology, none of these pathways exist in isolation so targeting just one will likely not be the best approach to slow aging. Some of the most promising techniques we can implement in our routines are exercise, fasting and cold exposure as they stimulate mild cellular stress and coactivate many of these longevity pathways.


Read more about David Sinclair’s insights into longevity and NAD+ along with the importance of a multitargeted approach to effectively address the complex biology associated with it.