My first car was my grandpa’s 1986 Chevrolet Celebrity. It had a lot of character. About 25% of the time, if you stopped at a red, the car would stall, and I became adept at putting it in park, restarting the ignition, and getting back into drive before the car behind me started honking. I was not surprised that an older car had these kinds of quirks. As time passes, we expect “wear-and-tear” on machines to cause certain types of system failures. We accept some of them and try to fix the ones that are too dangerous. You would probably not be surprised to hear that it is theoretically possible to keep a car running forever if you were good about maintenance and willing to replace any parts that wore out. Irv Gordon demonstrated the potential longevity of vehicles when he earned a World Record for driving his 1966 Volvo P1800 3,200,000 miles. Most of us would never put so many miles on our cars because it would be so expensive, but not because it is impossible.
However, when we think about the human body, we are more pessimistic about the potential of dramatically extending the lifespan, even though the average lifespan of a human is longer than the average lifespan of our cars. The potential lifespan of a human has gradually increased due to medical technology, but not many people I talk to seem to be super optimistic that we’ll be able to push our lives to be much longer than 120 years.
I study a lot of physiology, which is basically the engineering principles of the body’s machinery. I think that where many people still see death as a quintessential fact that defines what it means to be human, I see death as a failure of a machine that we don’t quite know how to fix yet. When we know how to fix it, it will be like the car situation — expensive, but it will be possible just to keep living. It is likely to be one of the more complicated social issues in our history as a species when this occurs. I think we should be considering it seriously.
First, consider that the biology of aging as a field of study is very young. It didn’t get going until the 1980s when researchers identified a biochemical, genetic pathway that modulated lifespan in several different animals for the first time. We are rapidly learning more about the causes of aging and potential therapeutic strategies to prevent it. This acceleration is hard to keep up with.
The field of aging research is starting to converge on a general framework that helps us understand why we get old. Natural selection occurs through genes, so our biology is optimized to reproduce within some time window. Multiple different biological mechanisms involved in aging are thought to interact with this principle. One that is very easy to understand is that harmful mutations to our genes that only manifest after the optimal window for reproduction easily accumulate. In contrast, mutations that cause negative phenotypes before or during reproduction are selected against.
A second interacting factor is that we evolved in a context of limited resources, so there was an evolutionary trade-off between growth, reproduction, and DNA repair and maintenance. Genes care about reproduction. Growth and DNA repair are only useful insofar as they benefit reproduction. Evolution optimized the balance between these three factors according to the available resources of our past instead of our present.
The last and most complex issue is that sometimes adaptations that benefit reproduction early in life might exhibit deleterious effects later. Evolution isn’t selecting nearly as well for traits after the peak of reproduction. For example, there is a neat little mechanism that helps prevent us from getting cancer. Cancer can occur when specific genes mutate due to damage or mistakes in replication. Since how many times a cell has replicated is correlated with its likelihood of developing cancer, biology invented cellular senescence. A cell tracks how many times it replicates, and then if it’s gone too many times, it stops replicating and broadcasts to everyone around it that it’s old and potentially dangerous. Immune cells usually then come in and clean them up. Unfortunately, more and more senescent cells accumulate with age, including immune cells, and eventually, the body can’t keep up. Then all this senescent signaling becomes problematic because it has adverse effects on the cells around them. The small warning signals accumulate into panicked mobs of cells, changing their function in response to the perceived damage and threat. This proinflammatory cascade can even make cancer more likely, the exact process it was designed to prevent. But it doesn’t matter; the system did an excellent job avoiding cancers before the peak of reproduction.
I am so optimistic about making real progress in aging therapies because we already have so many “anti-aging” mechanisms built into our biology. Nature has handed us a lot of great strategies to tackle aging. The hardest part of the work is already done.
Comparative biology is a valuable way to identify outliers in nature that we can learn from. Unfortunately for us, humans are already one of these outliers. We already have much longer lives than we ought to, and so we have to look to even more extreme outliers than ourselves to gain new insights. One of these even more extreme outliers in aging is the naked mole-rat. Naked mole-rats live on average ten times longer than their close evolutionary relatives. Even at that astounding age, it’s unclear that aging really plays any significant role in their death. They die from infections, starvation, predators, or assassination, not from the age-related diseases that kill many of us. The probability of death is stable across the entire life of the naked mole-rat. Figuring out what is different about them has been a recent pursuit of aging researchers.
One very important discovery made in 2018 is that naked mole-rats still have cellular senescence. That discovery was heartening in some sense. The fundamentals are the same; we may be able to dramatically increase our healthspan through minor tweaks to our physiology. So what things do seem different? Much of the story seems to be in the amount of resources naked mole-rats evolved to devote to DNA repair. Their DNA damage response works better.
So what sorts of tricky hacks evolved? You might not be impressed. Nature is a lazy engineer, preferring to copy and paste from already completed projects rather than inventing a completely new solution. We share a protein with naked mole rats whose job is to activate antioxidant and DNA damage repair genes. That seems like a beneficial gene. Naked mole-rats copied it, so now they have three copies, which is thought to increase the baseline expression of the gene. Awesome. What else? Both humans and naked mole-rats have proteins that label damaged parts of the DNA to be fixed. Naked mole-rats express more of this protein, which makes DNA damage repair faster. There are a few other hacks like this, including better-behaved senescent cells and preventing the accumulation of epigenetic errors, but I hope you’re starting to see my point. The solutions seem within reach. We don’t have to rewrite our genomes. We just have to figure out ways to coax our own biology to use the solutions that it already has.
Another telling discovery that made headlines some years ago was that infusions of young blood in old animals reversed some markers of aging. I think it made headlines because of its entertaining vampiric and dystopian undertones. It was just too easy to imagine billionaires pumping in the baby-blood every day after a joyful jaunt to outer space. But the discovery was fascinating to scientists for a slightly more subtle implication. There seemed to be some substance circulating in youngsters that was actively working against aging. Aging, it seemed, was more than just acquiring irreparable damage. The body knows, at least a little bit, how to repair itself. We just need to figure out what it’s doing.
Researchers are rapidly developing these “coaxing” strategies that utilize the built-in signaling mechanisms intrinsic to our cellular biology. For example, we have identified many molecules now that act as “senolytics,” which modulate the function of our biology in some way to selectively induce the death and clearance of senescent cells. Since so much of the dysfunction in aging seems to start with an over-abundance of senescent cells, there is hope that these therapies will help with aging generally. Most of this work has been done in the last five years, so it’s still early in the research, but the strategy looks promising.
Another strategy involves cellular rejuvenation. An incredible Nobel-prize-winning innovation was made in 2006 by Shinya Yamanaka, who discovered that exposing adult cells to certain proteins (now known as Yamanaka factors) would turn the differentiated adult cells back into stem cells. This technology has a lot of promise for many uses but has recently been identified as a potential aging therapy. The logic of it is really cute. When you expose cells to these Yamanaka factors, they seem to reverse their development and eventually look like embryonic cells…so what if you just stop that process a little bit early so that the cells look like they’re from a spry undergraduate instead of an embryo. Incredibly, this seems to work in cell culture. It’s still too early to tell if this will pan out in living humans and how dangerous it is.
These are just two strategies of a growing list of ideas, including activating Sirtuins, increasing NAD+ levels through supplementation, and metabolic enhancement through drugs like metformin. I won’t go into all the mechanistic details of these ideas, but I’m very excited and optimistic about this rapid development of therapeutic strategies that can be integrated and stacked on top of each other. These are not mutually exclusive ideas.
However, I think a major area where much more development is needed is aging specifically in the brain. Unlike much of the rest of the body, we only replace neurons in a few particular regions. “Reversing” the development of our brain cells, ala Yamanaka factors, might not be the best idea because we might expect that all those age-related changes to our brain cells also contain a lifetime of memories and learning. Keeping the rest of our bodies in good working order should do some good towards keeping our brains healthy, but eventually, I think we will need specific strategies for the cells that we can’t easily replace. We know many processes that kill our neurons begin from dysfunctional external environments like rampant inflammation from aging endothelial cells or over-active microglia. I’m not even sure that anyone has observed much age-related dysfunction in neurons in isolation. It’s even possible that our neurons could survive much longer than the rest of our tissues. Since neurons cannot be replaced, there would be intense evolutionary pressure to repair any damage very quickly. If that were the case, we would have another “outlier” to study, even more closely matched to the rest of our human biology, that might help shed light on how to increase helpful processes like DNA repair. We can simply ask, “how do neurons do it?”