Shahaf Peleg
Losing our personality is a great challenge of ageing.
My life up to now, like anyone’s, could be summed up in a series of snapshots, memories of the highlights that make me who I am. For example, when I was two years old, I learned to count, and learned the hard way that numbers are quite important when they are associated with a bus line. By the age of six, I learned how to play chess and could quickly beat my dad. Growing up, I played basketball and by the age of 13 I could touch the rim of a basketball hoop. At 19 years old, instead of enjoying college life, I was training to camouflage an army tank, wearing full gear in 40-degree heat.
Fifty years from now, it is likely I will not be able to do all of this. Even worse, there is a good chance I will not be able to remember these experiences and share them with anyone. I may never even remember writing this very article on ageing.
The prospect of gradually losing one’s personality is difficult to endure. What is life without memory? We work very hard to evolve our personality for years and yet we seem helpless to avoid losing it, bit by bit, as we get older. This is one of my main motivations to study ageing and, through my research, find new ways to extend our healthy life span and even prevent some of the damage ageing does to us. The key is to understand what happens when ageing starts, before it accumulates too much irreversible damage.
So what do I do in the lab and how do I try to improve our healthy life span? I investigate the connectivity between metabolic activity and chromatin remodeling during early ageing. Now, I am fully aware many of you will now say, “You what?” So, I’ll use some metaphors to clear it up.
What’s really going on as we start to age?
Just like cars (We will come to cars again later, as well!), we need fuel, or energy, to keep us going. The food we consume is first processed into smaller molecules. These are then broken down at special locations in our cells, called mitochondria, that create new molecules possessing the needed energy. Known as metabolites, these make us very much alive. To most scientists, when you mention metabolic activity, it’s all about energy production. However, these metabolites have another interesting property, which is sometimes overlooked by scientists.
Some metabolites can be carried away from mitochondria by certain proteins we refer to as messengers, as they do, indeed, carry a message to our DNA. The metabolites can then be attached to proteins called histones. Histones are special, because they organize the structure of our DNA. The attachment of metabolites to histones modifies the histone (hence the name “histone modification”). This changes the DNA structure and results in switching our genes on and off.
Double-stranded DNA (1) is wrapped around histones (2), which give
it structure and help control the switching on and off of genes.
You can think about it as going to listen to classical music. You first notice the musicians sitting on their chair, waiting. Only when the conductor arrives can he coordinate them to make meaningful music. Individually, their music is too simple. Together, without guidance, they create something unpleasant. The conductor is the key. If genes are the musicians, our histones are the conductor. And such action of our histones is known as chromatin remodeling.
The flexibility of our genes to be turned on and off and be coordinated by the histones allows our body to react to the environment. For instance, activating and deactivating new genes for short periods of time, we are able to form new memories! Our conductor can indeed make us do great things. Alas, as we get older, the conductor starts to make mistakes…and it is not clear to us why. What could cause this?
During early ageing, the function of our mitochondria (the powerhouses that create energy in our cells) starts to change for unknown reasons, and with it, the metabolites. As in a domino effect, when the metabolites change, it impacts the histones. Consequently, the ability to organize and control our DNA and genes with harmony is disrupted. Such disruption creates a new need for energy to solve the new problem, which causes the mitochondria to work harder, which… — which, in other words, leads to a vicious cycle of cellular damage until an irreversible point of no return is crossed.
You can compare it to a car. A younger car goes fairly smoothly on the road. But, in ageing, the road becomes steeper and steeper, and in order for the car to maintain its speed, it actually needs to invest more power. Eventually, you can imagine the stress on the engine will be too much, and the car will slow down and eventually stop.
Making our own invisibility cloak
In the Harry Potter novels, one of the mythical Deathly Hallows was an invisibility cloak, which, legend claims, could hide its owner from Death. Could we have our own, and delay the meeting with death? In other words, what can we do to avoid the damage resulting from mitochondria working overtime?
It is difficult to change our energy production without side effects. The same is true about changing histone modification. However, what about targeting the messengers that are connecting the two? Just like in wartime, taking down the messages between the high command and the field soldiers can be enough to win the war. Can we apply the same principle to our ageing problem? Indeed, my recent work in fruit flies demonstrated that reducing the messengers (but not shooting the messengers dead!) results in an increase in healthy life span. In fact, such flies also maintain better motor activity when they get older, compared to flies that are not treated. We next plan to see if we can use the same principle to extend the life span of animals more genetically akin to us, such as mice.
My current research aims to develop drugs targeting the messengers that will allow us to slow down the damage, live healthier, for longer, and, most importantly, to keep our personalities just a bit further into old age. If you wish to stay tuned, follow me on Twitter!
For a short video where I explain the concept:
For more scientific reading about my research:
The Metabolic Impact on Histone Acetylation and Transcription in Ageing. Trends in Biochemical Sciences, 2016. [Open Access]
Life span extension by targeting a link between metabolism and histone acetylation in Drosophila. EMBO reports, 2016. [Open Access]
Altered histone acetylation is associated with age-dependent memory impairment in mice. Science, 2010.
About the author:
Shahaf Peleg (@DocLarus) is a fellow of the AXA Research Fund who has always been fascinated with ageing. In 2010, he did his PhD at the European Neuroscience Institute in Goettingen, Germany, as part of the Max Planck Research School program for Neurosciences. In 2011, he moved to the University of Munich (LMU), where he continues to work on new angles to extend healthy lifespan. He is currently a visiting scientist at Tokohu University in Sendai, Japan. Shahaf is the 2011 Schilling Award recipient of the German Neuroscience Society.
