The Science

For more information, refer to the longevity FAQ.


Introduction

As you get older, the chance that you will die goes up.
As you get older, the chance that you will die from certain diseases also goes up.
Why does this happen?

A simple explanation would be that, like an old car, you accumulate damage in a random fashion.

However, there are many simple things that we can do to make animals live longer. Why? We don’t really know.

Eating less makes mice live longer.


Some genes, when mutated, make mice live longer,

A few drugs, approved for human use, also make mice live longer.

There are others - we will cover them below.

So what is the study of aging?

I sum it up as the following: trying to figure out what kinds of damage accumulate with age, how to reverse that accumulation, and the search for switches that we could flip in human biology to increase lifespan.

Research areas in longevity

Caloric Restriction

 

at a glance: eating less, in a variety of ways, can make you live longer - but is your body just using number of calories as a signal?

 

In the 1930s, investigators wanted to do an experiment to see if stunted growth rates during the Great Depression might impact lifespan. They tested this in rats by feeding them less food than they would normally eat. To their surprise, this actually made the rats live longer! This was a seminal discovery. For the first time, we changed the environment of an animal to make it live longer than it normally would. 

 

Since then, investigators have tried to uncover how this works. The effect depends on what genes you have, what you are eating and how much less you eat. If you take many genetically distinct mouse strains and put them on the same diet (cutting calories by ~40%), sometimes fewer than 1/5 of the mouse strains live longer. Diet composition also plays a role. Just decreasing protein or a specific amino acid, while keeping total calorie intake the same, can result in a lifespan extension in mice. Feeding mice a ketogenic diet also seems to help. Decreasing food intake by too much will result in starvation, so finding a diet that works can depend on the situation.

 

While long-term human studies are sparse, investigators have run two caloric restriction experiments in monkeys, one of which showed promising results for an increase in survival. To avoid the difficulty of continuous dieting, fasting ~8+ hours a day, or 5 days/month, or on a variety of different cycles might also be helpful. This is called intermittent fasting. Medically, intermittent fasting may aid recovery during chemotherapy. Some longevity-related pathways involve sensing amino acid levels, so it is possible that a specific biological process, not total calorie intake, controls the increase in lifespan.

 

Insulin/IGF

 

at glance: genetic pathways related to growth and insulin signaling are linked to aging

 

In papers published in 1983-1993, investigators introduced the concept that a gene could control lifespan. I got my start in science when one of the founders of this field, Cynthia Kenyon, agreed to let me work in her lab as a 12 year old kid. I'll always be grateful for her kindness and mentorship. Previously we'd known that caloric restriction could make animals live longer, but Kenyon and other scientists including Michael KlassDavid Friedman and Tom Johnson found mutant genes that could make worms live longer. The gene that Kenyon found encoded a protein that is similar to insulin-like growth factor and insulin receptors in humans. In mice, mutating members of both of those pathways can increase lifespan. One of the longest-lived mouse mutants we have today is a dwarf mouse. In one study, people with similar dwarf mutations seemed to suffer less age-related disease than their non-mutated relatives.

 

I'm fascinated by the fact that many drugs which have been developed for diabetes, without any thought for their use elsewhere, turn out later to be relevant to aging. Good examples of this are metformin and FGF-21. Metformin is a small molecule used to treat Type 2 Diabetes, and FGF-21 is a protein in your blood that can increase lifespan in mice. We are still figuring out how the insulin/IGF pathway works, in particular what kinds of molecules might be driving the lifespan effect that we observe. 

 

Parabiosis

 

at a glance: young blood makes old mice healthier, but why?

 

Dracula wanted to drink young blood, but what does that have to do with aging? A paper published in the 70's showed that linking old and young female mice so that they share a bloodstream increased lifespan. Decades later, in 2005, scientists at Stanford showed that this procedure might help old muscle stem cells repair wounds. Then, in 2011, a succession of papers came out showing that this procedure and others like it (such as injecting young blood into old mice) made mice better at remembering things, and improved heart and muscle function with age. These discoveries increased excitement and interest in the field, and lead to a wave of startups. 

 

Investigators in the field have proposed many possible causes for this phenomenon. Proteins, small vesicles, or cells in the young mouse cleaning the blood of the old mouse might all be part of the effect. Many companies are trying to figure out whether there is a special protein or molecule involved. The big questions to resolve will be whether we can isolate a few key factors that are responsible for the parabiosis effect, and how many of the longevity-related phenotypes will translate to improve human health.

 

Senescence

 

at a glance: a fraction of your cells get older than the others, so we'd like to eliminate them

 

As you get old, so do your cells. But some of your cells get old in a way that is much worse than the others. You may have heard of a thing called telomerase. If you remember correctly, it's the thing that keeps the end of your DNA long enough that your cells can still divide. When one of your cells runs out of telomerase, it can't make many more copies of itself. If the cell sticks around, refuses to die even when it stops working, and starts secreting signals to the immune system, we call that a 'senescent cell'.

 

What happens when you get rid of these cells? Some animals that age faster than normal have a lot of these 'senescent cells' and are good experimental models in which to ask that question. In 2011, a group from the Mayo Clinic cleared out many of the senescent cells in one of those animal models, and found that the resulting mice were healthier in old age (among other things, they did not get cataracts and bent spines, which typically emerge in old age). In 2016, the same investigators found that getting rid of senescent cells in normal mice made them live a longer healthy lifespan. Knocking out senescent cells is tricky, because they don't have many unique identifiers. Companies are working to either find things empirically that kill senescent cells, or figure out specific mechanisms by which to try to destroy them.

 

Autophagy

 

at a glance: the garbage disposal unit of the cell worsens with age, improving it might increase healthy lifespan

 

Your body makes a lot of junk, on the molecular level, and cells need to clean this up. Just increasing the expression of one protein that helps to clean up this junk was enough to make mice live ~17% longer. Cells recycle old proteins and other molecules into a big vesicle, called a lysosome. It contains many proteins, and their job is to chop up old cell parts that it engulfs. Genes for proteins that do work in the lysosome are mutated in diseases such as Parkinson's. So improving this process has immediate relevance to neurodegenerative disease. As the lysosome gets older, more junk builds up in it that it cannot degrade. Finding ways to make more lysosomes, or help lysosomes degrade junk, may be interesting therapeutic avenues to pursue. 

 

Hypothalamus

 

at a glance: a surprising number of things can increase lifespan when only changed in the brain tissue

 

Changing something just in the brain can be enough to make a mouse live longer. If the hypothalamus thinks it is too warm, for example, it can decrease the core body temperature of a mouse, resulting in a slightly longer lifespan. Changing the level of a variety of genes in a brain-specific way can also make a mouse live longer.We know that the hypothalamus makes something called growth hormone releasing hormone (GHRH), which is in charge of, well, releasing growth hormone. Growth hormone appears to be closely tied to lifespan, so the hypothalamus could be an important control point. One interesting question is how much you can affect the lifespan of a whole organism by just making changes to the brain.

 

Reproductive System

 

at a glance: removing the ability to reproduce can increase lifespan

 

10 years ago, one of the first projects I worked on was trying to understand a weird fact about reproduction in worms. If you take little worms and get rid of their gonads (I know, it's weird), they live ~60% longer than normal. But this only works if you get rid of the stuff inside (sperm/eggs - these worms are hermaphrodites, which means they carry around both). If you get rid of the whole thing, lifespan goes back to normal.

 

This isn't restricted to worms. From court records of Korean eunuchs, the eunuchs tend to live longer than their contemporaries by 14-19 years. Some people have tried to do things such as transplant young ovaries into old mice, to see if that helps (it might add a bit to lifespan). There are also many reports showing that when you make things live longer, fertility goes down. There might be a tradeoff (fertility takes away resources that could be used for something else), or a signal coming from the reproductive system that tries to hold up aging if it is damaged.

 

Mitochondria

 

at a glance: mitochondrial mutations impact lifespan in counterintuitive ways

 

You may have heard mitochondria referred to as the 'powerhouses' of the cell. It's funny, they do literally run like a dam generating hydroelectric power! - They pump protons (positively charged particles) one way, then use them as they slide back to run a kind of motor that makes a small energetic molecule used by many entities in the cell. One concept that comes up when people talk about mitochondria is 'oxidative stress' - the idea that if molecules are very reactive (say they have oxygen, acquire some extra electrons, and now want to discharge them onto other molecules), they are likely to interfere with a lot of other molecules in the cell that should be left to their own devices.

 

Weirdly, the story has turned on its head over time. It's true that it is bad to pump an animal full of reactive oxygen species, and that you can make a mouse live longer by increasing the level of proteins that are supposed to clean up mitochondria. But you can also mutate things that should be helping the mitochondria, and end up increasing lifespan! It's counterintuitive, and one hypothesis is that a little bit of stress is good because it forces your cells to put up their defenses and ramp up production of molecules that neuter the reactive oxygen species. But we don't really know. 

 

Sirtuins

 

at a glance: sirtuins can change DNA and increase lifespan

 

Sirtuins add tags to the structural protein balls that DNA wraps around. It sounds odd, but think of yarn wrapping around a cardboard tube. When they add tags to the DNA yarn ball, it changes how the DNA is folded and expressed. So one of their actions is to control what genes do.

 

Sirtuins were first discovered to increase lifespan in yeast, and seem to also do so in worms, flies and mice. They depend on NAD to do their job, so when you see people talking about NR or other precursors of NAD, you can think about them as also helping the sirtuins do their job. You can extend lifespan a little bit in mice by giving them NR in old age.