Within a species (intraspecies), being a bigger variant or breed means living less long. Between species (interspecies), being a bigger species or genus means living longer.
This is almost universally true, at least among mammals.
2. Big humans are more prone to metabolic disorders, heart problems, and cancer than small humans.
3. Horses live less long than ponies, even though they’re the same species (up to 10 years difference).
5. Potbellied pigs, which are 125+ pounds, live twice as long as 300+ pound domestic pigs.
1. The longest lived mammals are all large, like elephants (70 years), whales (90 years), and hippos (50 years).
2.The shortest lived mammals are all small, like mice (2-3 years), shrews (1-1.5 years), and rats (2 years).
3. The middlest lived species are middle sized, like dogs (12 years), goats (18 years), or capuchin monkeys (25 years).
Neither of these patterns holds all the time, of course.
Intraspecies, there are some bigger individuals that live a long time and some smaller individuals that die young. There are also limits to how small an individual can get and still live a long time, as individuals that are too small (like “teacup” dogs) tend to get severe health problems.
Interspecies, there are minor outliers: cats live longer than dogs, on average, and donkeys live longer than cows. But, there are also some major outliers: humans live up to 120 years, way longer than their bigger cousins, gorillas, who live up to 50 years in captivity. Naked mole rats live up to 35 years, way longer than their bigger rodent cousins, capybaras, who live 10 years in captivity. Finally, bowhead whales live up to 200 years, twice as long as blue whales, which are much larger than them.
However, these two patterns hold often enough that they’re interesting. What gives? Why does lifespan decrease with body mass intraspecies, and increase with body mass interspecies?
It seems easier to explain the intraspecies pattern. Bigger animals have more cells, so more chances for things to go wrong, like cancer. They also have more mass, placing greater mechanical stress on their organs, bones, and joints. Finally, they have more surface area, resulting in a greater chance for infections.
For the interspecies pattern, we have to rely on more pseudoscientific explanations, like the idea of a billion heartbeats over the course of a lifetime (so a slower heartbeat results in a longer lifespan) or some sort of handwaving at DNA repair rates and methylation.
Unfortunately, neither explanation can explain both the intra- and interspecies pattern. An explanation that associates smaller individuals with a longer lifespan has to explain the incredibly long lifespan of elephants. An explanation that associates bigger species with a longer lifespan has to explain why big dogs, with their slower heart rate and slower metabolic rate, have a shorter lifespan than small dogs.
Instead, to come up with a unified explanation, we have to look for another factor. To my mind, it’s this: all else being equal, being bigger is associated with a shorter lifespan, due to the stresses mentioned for that intraspecies relationship. However, all else isn’t equal. Bigger species are much more likely to be k-selected, meaning that they have an evolutionary strategy that involves a few children that they spend a lot of energy on. Baby elephants require a lot more time and energy to raise than baby rats, because baby elephants have to grow a lot more to become adults. Evolutionarily, that promotes a longer lifespan for the elephant, as the momma elephant needs to live long enough to raise its baby. So, interspecies body mass being positively associated with longevity is because of k-selection.
However, that’s just why big species live longer than small species. It’s not how big species live longer than small species. In order to answer how big species live longer, we need to bring in another factor: how to extend lifespan within an individual. There are really only 3 ways of reliably doing so: caloric restriction, rapamycin (an immunosuppressant), and metformin (a drug that suppresses glucose production by unclear mechanisms). Caloric restriction has the most support, followed by metformin and rapamycin.
What’s the similarity between caloric restriction, metformin, and rapamycin? All of them downregulate the immune system, specifically the lymphocytes, part of the adaptive immune system. Rapamycin directly inhibits lymphocyte proliferation; caloric restriction indirectly downregulates lymphocytes through leptin; metformin indirectly and directly regulates a variety of immune system functions.
This is not a coincidence. Guess what the difference is between the immune systems of large mammals and the immune systems of small mammals? Large mammals have a lower concentration of lymphocytes and a higher concentration of neutrophils. Guess what’s unique about the immune system of bats, a notoriously long lived mammal species, vs. other small mammals like rodents? Bats likely lack natural killer (NK) cells, one of the key lymphocytes. Naked mole rats also lack NK cells. Meanwhile, guess what’s different about the immune system of humans vs. that of chimpanzees, their shorter lived cousins? Chimps have more active/potent NK cells than humans.
Lymphocytes, specifically NK cells, are bad for longevity. This is because lymphocytes in general are one of the main causes of apoptosis, or cell death, even after mildly stressful activities like exercise. NK cells are especially harmful for longevity because they are especially prone to causing apoptosis. NK cells are on a hair trigger: when they’re summoned, they destroy any cell that doesn’t display signs of not being infected (if that sounds confusing, just imagine the navy sinking any ship that doesn’t have a flag, whether or not it has a pirate flag).
Destroying cells on a hair trigger is a good way to ensure short term survival in an environment with a lot of pathogens that are constantly taking over cells. This is a bad way to ensure long term survival. Creating new cells constantly is difficult and prone to error, which can lead to malfunctioning cells or cancer.
Intraspecies, immune systems are the same, so size conveys no advantages. Interspecies, evolutionary pressures downregulate lymphocytes, resulting in increased longevity.
So, what does this mean for interventions to improve longevity? Well, we should probably focus on deliberately targeting NK cells for destruction. Unfortunately, there doesn’t seem to have been a lot of work in deliberately doing so. Interventions like rapamycin do so by accident, but highly targeted interventions (i.e. through monoclonal antibodies) in NK cells have been lacking, probably because there’s been no obvious need to.
Fortunately, we know that it’s at least possible. Tumor cells have a biological need to evade NK cells, because NK cells are the most common cause of early tumor cell death. To do so, tumor cells rely on a variety of tactics, including releasing TGF-β, HLA-G, prostaglandins, adenosine, and various kinds of extracellular Vesicles (EVs) and microRNAs (miRNAs).
Of these, the best understood are prostaglandins, which are hormone-like substances that cause vasodilation, inhibit clotting, and can suppress NK function. While they are best known for their role in inflammation (e.g. NSAIDS like ibuprofen inhibit prostaglandins), synthetic prostaglandins like misoprostol are also used for inducing childbirth or abortions and preventing and treating gastric ulcers. As you might expect, misoprostol does inhibit NK cells (or at least CD56+ cells, of which NK cells are a type), at least according to a very sketchy Chinese paper from 2001.
So, if we want to take advantage of nature’s way of promoting longevity, namely downregulating NK cells, prostaglandins would likely be a good place to start.