Everything That Rises

“Happy families are all alike; every unhappy family is unhappy in its own way.”  – Leo Tolstoy, Anna Karenina (1875)

The trouble with looking for one single root cause of aging is that – like everything else in biology – the lifespan of an organism is the result of a complex web of interactions.  It’s a tapestry and pulling on any of a multitude of different strings can lead to its unraveling.  I would like to propose the Anna Karenina Principle of Aging, which states that all short-lived species are short-lived in their own unique way.  There are a multitude of different aspects of cell and tissue function that can ultimately go wrong, each of which can shorten the lifespan of an organism in its own unique way.  Both fruit flies and worms age rapidly and die – they lose homeostasis (an internal biological balance) – but there’s no reason to believe that the aging process in either species has to be the same.  There are just too many options for things to go wrong that no two sets of options have to resemble each other.  The corollary of course is that all long-live species likely resemble each other in some key ways.  So many ways to get it wrong, but only a few ways to get it right.  (This can also be stated as the Flannery O’Connor Principle: “Everything that rises must converge.”)  The evolution of long life can likely be viewed as convergent evolution where different long-lived species individually converge on the maintenance of long-term homeostasis.  Most researchers who study aging do so by using short-lived species (Drosophila, Caenorhabditis elegans,  Nothobranchius furzeri, etc.), largely because the organisms are small and easy to care for, and the experiments can be completed in a timely manner.  I propose however that much more can potentially be learned from studying long-lived species.  We need comprehensive comparative studies of the longest lived species on this planet, especially the things in the same class as ourselves – the mammals.  We don’t just need to determine what the short-lived species are getting wrong (although that is valuable information); we need to determine what the longest-lived species are getting right.

Recent Articles – Autophagy, Senescence, and Aging

Interesting connections among recent science news articles.  Cigarette smoking promotes lung aging by interfering with autophagy (cell component degradation and recycling) in lung cells and triggering apoptosis and cellular senescence.  Similarly, here’s a paper showing that clearance of senescent cells rejuvenates lung tissue in mice.  Senescent cells secrete a toxic mixture of molecules (the senescence-associated secretory phenotype), which – among other things – induces inflammation and the removal of senescent cells by the immune system.  Tying together the previous two papers, here’s a recent Cell paper showing that defects of mitochondrial autophagy (mitophagy) promote inflammation and cell clearance by the immune system (here’s the pop-science version since the primary source is behind a paywall).  Here are two questions:  (1) Do similar defects in autophagy also lead to cellular senescence?  (2)  Autophagy (and mitophagy) increase following calorie restriction.  Is part of the benefit of calorie restriction a decrease in inflammation due to this mechanism?  And the long-standing big question of (3) why do senescent cells accumulate during the aging process?  Is it from a decline of the immune system?  Or is it something else?

The Extrinsic Mortality Theory of Aging

Aging is the inevitable loss of homeostasis in an organism that ultimately leads to its death, and in the broadest sense you can view aging as the result of a factor called extrinsic mortality. This factor is a way of saying that even if an organism was biologically immortal (no set lifespan), you would still only expect it to live a finite amount of time based on the threats in its environment. The world is a dangerous place – creatures eat each other, are infected by pathogens, freeze or starve to death, etc. There is always a certain risk based on your ecological niche and immediate surroundings, which should eventually catch up with you, statistically speaking. Driving on the Interstate falls under that category.

So even a biologically immortal creature has a set lifespan determined by its environment, and once there is a set lifespan you have a point beyond which evolution is no longer selecting for traits. Evolution only has to make each species good enough to grow and reproduce within the period of time that it can be statistically expected to live – thanks to extrinsic mortality. Traits promoting a longer lifespan than the statistical limit cannot be selected for. This cutoff on selective pressure also means that even if you started with a planet populated entirely by biologically immortal creatures, biologically-set lifespans would eventually evolve because traits promoting survival and reproduction in the short term would be selected for, whereas traits promoting long term survival would not.

This cutoff is also the origin of the three main biological factors contributing to aging: (1) antagonistic pleiotropy, which is the existence of genes that are beneficial in early life and detrimental in later life, (2) developmental inertia, which is where the same processes that guide development begin to simply drift in an unregulated manner after a certain age, and (3) the accumulation of irreversible macromolecular damage, which occurs because our bodies have no selective pressure to repair any type of damage that accumulates slowly enough to only be life-threatening late in life. So set lifespans evolve, not because dying by a certain age has any evolutionary advantage, but because traits that would let us live longer cannot be selected for.

When you stop and think about it, extrinsic mortality explains the specific biological lifespans of different species. Compare the extrinsic mortality of a giant redwood to a C. elegans, or that of an alligator to a fish. Our lifespan is probably the result of the environmental dangers during the time when Homo sapiens evolved – the Pleistocene. Also this means that if an organism’s environment becomes safer, then it should gradually evolve a longer lifespan to match the new conditions, since longer lifespans always have the evolutionary advantage of providing more opportunities for reproduction.

Here are a few predictions based on this theory:  (1) Animals in stable environments will have a longer natural lifespans than animals in unstable environments (subject to droughts, flash-flooding, etc.), and (2) animals with few natural predators will have natural lifespans that are longer than animals that are subject to much predation.

Programmed Aging

The maximal lifespan of a creature is under some form of genetic control, as is evident from the characteristic lifespans associated with each species.  Laboratory mice live on average approximately 2 years in captivity.  Indoor cats live about 14 years, horses live about 30 years, and humans (in the United States) live about 80 years.  This length of time is a signature specific to each species, and like all other signature traits it must be a consequence of genetic makeup.  Lifespan is at least partially genetic – check.  The question then becomes: which genetic elements are the most responsible determining lifespan, and why?  One immediate theory that often arises from the genetic aspect of lifespan is that all aging organisms harbor “suicide genes.”  In other words, genes that have been selected by evolution specifically because they kill the organism after a certain length of time.  Theories of suicide genes often include the idea that aging has evolved as a means to benefit offspring by selectively removing older individuals from a population, thus freeing resources such as food from increased competition.  (The argument for removing older, as opposed to younger individuals can be made assuming that older individuals potentially harbor more time-dependent DNA mutations and macromolecular damage that would limit their potential to produce fit offspring.)  I would like to make a short argument against this theory based on a few predictions.  (1) Genes that specifically removed an individual for the good of its offspring would have difficulty becoming the dominant allele in a population since they would confer the same benefit to all members of the population, while at the same time removing members of the population that specifically harbored that allele.  (2)  Environments with geographically-limited resources, such as islands, should have a higher number of species with comparatively short lifespans than environments with less competition for resources, which as far as I can determine from the literature is not the case.


Lack of A Unified Theory

“A problem well stated is a problem half-solved”  – Charles Kettering

The biggest current obstacle to extending human lifespan is a lack of understanding of what aging is.  The question of “why do we age” is still unanswered, which is rather embarrassing for the field of biology as a whole when you think about it, because the process of aging is so universal.  The problem is similar to observing that all animals have lungs, but lacking any unified theory as to how lungs evolved or what purpose they may serve.  A basic understanding of lung function and physiology would be a minimum requirement before doctors could go about systematically treating any lung-related diseases.  It is not much of an exaggeration to say that we are in a similar state today.  So many of the diseases that plague humanity are diseases associated with aging, and yet a truly satisfactory understanding of why we age is still absent.  Scientists know a multitude of individual events that happen during the aging process – many of which are even common among a broad range of living creatures – and yet a unified theory of aging is still absent.  (Note: The lack of theory isn’t from a lack of effort.  There are literally dozens of published hypotheses attempting to explain the universality of the aging process.  What we lack, in my opinion, is one answer that incontrovertibly encompasses all of the evidence.)

I have heard the argument that the theory aspect of aging isn’t critical for extending human lifespan, since it’s only the details – the specific events that go wrong during the aging process – that need to be treated.  I believe that this statement might at best be half-true since it’s an issue of proximal causation versus ultimate causation.  The proximal cause of an event is the most immediate thing causing that event.  The proximal cause of a sinking ship might be a fist-sized hole below the waterline of the hull, and the presence of that hole might be the only thing you need to know to patch it and keep sailing.  The ultimate cause however is the highest-level thing responsible for an event.  For the ship example, the ultimate cause might be icebergs, and knowing that you are sailing into iceberg-filled water, and taking steps to avoid slamming into them, is likely the best strategy to continue sailing long-term.  We know many of the proximal causes of the aging process.  What we lack is a ultimate cause to guide an anti-aging strategy.