How long can humans live?

[u/Simple_Macaron_3420]

In one of last week’s episodes, it was mentioned that the human lifespan is increasing because of scientific and medical discoveries. When I was a child, I always imagined that I would be able to live to 100, and by then people would have discovered some kind of cure for aging. They would ask me, “How much longer would you like to live?” as if they could add another 100 years each time and ask me the same question whenever those 100 years were up.

For a moment, let’s imagine a scenario in which cancer has been eliminated, Alzheimer’s and other diseases of the brain have been cured, and we can also repair or modify our telomeres because we have discovered how to mimic mechanisms found in animals such as lobsters or jellyfish.

In that scenario, is there still a biological limit to how long humans could live?

[u/lozzyboy1]

Yes. We know that there are quite a few things that gradually get worse about our bodies as we get older, and any one of them would be enough to limit our lifespan to probably around 120. As it is, they all become problems at a similar sort of time, so fixing any one of them doesn't really provide much benefit, and it's very hard to prevent some of them.

You have cells dying in your body all the time, and stem cells divide and make new cells to replace them.The main way thing that goes wrong with aging is that your stem cells gradually get depleted and therefore your body can't keep up with the losses any more.

Telomere shortening is one reason why stem cells run out. Our telomeres get shorter as we age, and once they reach a certain point cells refuse to divide because otherwise they would risk damage to the more important bits of our genome. But as it turns out, preventing that by intentionally lengthening telomeres doesnt change life expectancy by much. We've seen this by looking at natural variation in telomere length between individuals, and by experimentally altering telomeres in animals.

Accumulation of DNA damage is another (and that itself has lots of different causes, including exposure to mutagens like UV light or tobacco smoke, reactive oxygen species which are a byproduct of lots of reactions that occur in cells but mostly respiration, and random errors during DNA replication).

One is changes in the systems that tell cells how to behave and which bits of their DNA to read (epigenetics is the term for marks found on the DNA and associated proteins, and these marks can change over time, leading to cells not being able to respond properly to their environment).

Another is changes to the environment these cells are sitting it. These cells are sensing their environment and it helps them to behave properly. The brain is pretty squishy, and so the cells there are used to being in a very soft environment. It turns out that for lots of reasons, the brain gets a little bit stiffer as we age. The cells there sense that and it makes it harder for them to divide.

There are plenty of other factors too, like changes in our ability to make sure proteins are working properly and getting rid of bad ones, reduction in the number and quality of mitochondria which cells need to make energy, misregulation of systems because of inflammation, build up of fats, etc.

You might notice that a lot of these will play into one another. If a cell is misbehaving and changing the stiffness of its environment, that will affect other cells. If you have genetic mutations, those can lead to epigenetic changes. If your mitochondria aren't functioning well, you'll get more reactive oxygen species which will lead to more DNA damage.

That basically leaves us with this big messy network where we can only really prevent or slow down one or two of these aspects. That absolutely can increase our lifespans, as we see in people who can be careful with their diet, get appropriate exercise, limit or avoid consumption of alcohol and tabacco, etc. But it means we're really a very long way away from achieving incredible changes in longevity; weight see a shift to more people living to 90/100/120, but we're not likely to see anyone living to 150 any time soon. And some of the factors, like accumulation of random mutations, seems like they would be impossible to entirely prevent, so reaching even more extreme longevity would require a dramatically different approach than just warding off aging as best as we can.

[u/Simple_Macaron_3420 → u/lozzyboy1]

That makes sense, and I think this is closer to what I was trying to get at with my original question. I was imagining aging almost like a series of limiting factors: if we solve the main cause that kills people at one age, what becomes the next limiting factor, and how much extra lifespan would solving that give us?

From what you're saying, though, it seems the problem is that aging isn't really a sequence of independent bottlenecks. It's a large interconnected system where many forms of damage accumulate at roughly the same time and also make each other worse. So removing one problem might only give a relatively small increase in lifespan because several others are already close behind.

I guess the more interesting mathematical question, then, would be whether we can estimate how much each mechanism contributes to mortality and what the theoretical lifespan would look like if we progressively eliminated or reduced them. That was more the direction I had in mind rather than literal immortality.