Humans have always been obsessed with the ability to live forever. Cultures around the world have myths about achieving immortality. Generations of Chinese retell the legend of a mortal named Chang’e drinking the elixir of life and becoming a god on the moon, while ancient Greeks wrote poems about Tithonus beseeching Zeus to have immunity from death. The quest for limitless life has captured the minds of countless storytellers, alchemists, and spiritual leaders.
Although Greek gods and magic elixirs do not exist, eternal life may be attainable. We need only look to the oceans for a fascinating example. In most open ocean waters on Earth, one can find a type of jellyfish called Turritopsis nutricula, also known as the “immortal jellyfish.” When it encounters unfavorable environmental conditions, the adult Turritopsis—normally overflowing with tentacles that evoke the image of the head of Medusa—simply sinks to the ocean floor and reverts to its juvenile polyp phase that resembles nothing more than a tiny clump of cells. Even more fascinating is that the jellyfish can repeat this process of regression and re-growth endlessly. To date, there have been no reported observations of its death due to aging.
The discovery of Turritopsis, along with many other recent observations of longevity, suggests that science may help us find the fountain of youth. With a host of new biological techniques and the rigor of the scientific method, investigators at UC Berkeley and around the world are poised to take the human race closer to everlasting life than we’ve ever been before.
Extending life (in a lab) is possible!
While the process of aging in all organisms is associated with gradual changes in physical appearance and capability, this process manifests itself very differently between species. For example, larger animals tend to live longer: consider an elephant’s average 60-year lifespan to a laboratory mouse’s two. Significant differences can be found within a species as well. Geographically distinct populations of humans can have very different life spans due to their different metabolic requirements and cultural traditions. Understanding the complex genetic, metabolic, and evolutionary mechanisms behind these observations requires expertise from a wide variety of scientific fields. What results is a multi-faceted approach that makes up a quickly expanding subfield in biology: the study of aging.
One of the most notable biological theories of aging came from biologist Thomas Kirkwood. Published in 1977, his landmark paper postulated that organisms sacrifice themselves in order to pass their genes on to their offspring. He found that our somatic tissues (those that have no function in reproduction, such as the brain or heart) sustain a lot of damage to conserve energy in order for our germline (reproductive organs, as well as sperm, and eggs) to prosper. Kirkwood hypothesized that damage to somatic cells at the expense of the germline results in aging. Because these cells don’t contribute to the reproductive fitness of an organism, they do not feel the same selective pressures from nature, and as a result are allowed to deteriorate by the organism.
Professor Andrew Dillin, a new faculty member in the Department of Molecular and Cell Biology, contributed evidence to this “disposable soma” theory by studying a species of roundworms called Caenorhabditis elegans (C. elegans). While a postdoctoral fellow in Professor Cynthia Kenyon’s lab at UCSF, Dillin and his colleagues used a laser to destroy two cells in the worm that give rise to its entire reproductive system. Worms that underwent this procedure lived 60 percent longer than those with intact reproductive organs.
Because of the worm’s small size and number of cells, scientists can map exactly where each cell is, what it is doing, and what its future fate will be at any given developmental stage. For example, the two cells that were destroyed by laser were precursor cells that can continuously divide throughout the worm’s development into sexual maturity. Simply getting rid of the sperm and eggs in laboratory worms that are commonly hermaphrodites was not enough. The ablated cells had to be needed by the worm to maintain a functioning reproductive system that generates more sperm and eggs, and thus act to regulate aging throughout the worm’s lifetime. “Getting rid of these precursor cells serves to divest metabolic energy,” explains Dillin. Since it is no longer needed to create offspring, this energy can instead be used to take care of the whole organism.
Knowing what cells they manipulated allowed Dillin and his labmates to genetically change the worms to track down the molecules required for this observation. Through this approach, they discovered that a gene called DAF-16 is the master regulator of life extension by germline depletion. Without the gene, removing the two precursors did not help worms sustain youth. This indicates that DAF-16 acts to promote increased lifespan but somehow is hindered by the reproductive system’s need for energy.
The reason for DAF-16’s central role in aging is probably due to its involvement in the molecular signaling pathway initiated by a much better known protein: the insulin receptor. Insulin is the body’s main metabolic signal. When it binds to receptors on the cell surface (primarily liver, muscle, and fat cells), insulin initiates a molecular cascade within the cell that tells the body to take up the glucose from food that is now in the bloodstream and convert it to energy. As a result, this signaling pathway is intricately connected to the overall consumption and metabolic requirements of the organism. Kenyon, Dillin, and others have shown that blocking this pathway in C. elegans can extend a worm’s lifespan by over two-fold.
Because of the dramatic extension in lifespan that results from rendering insulin receptors nonfunctional, Kenyon termed the gene encoding for insulin receptors the “Grim Reaper gene.” The insulin pathway is evolutionarily conserved throughout the animal kingdom. Therefore, it was not surprising that other labs have since found that mutations in the insulin receptors of flies and mice can also lead to life extensions in these animals. These “old” mutants appear youthful with no hint of physical changes that are usually associated with aging.
Through these animal studies, a surprising picture has emerged: the voracious energy requirement of the germline and the overall energy production of the body from food intake, two seemingly unrelated bodily functions, converge onto one protein—DAF-16—to regulate aging. This led scientists to focus on one of the most important processes in aging research: metabolism.
Caloric restriction and cellular stress
Danica Chen, Assistant Professor in the Department of Nutritional Science and Toxicology, was particularly interested in the relationship between metabolism and aging when she learned about research performed in the Kenyon lab and others. At the time, results obtained from these laboratory animals were directly related to observed phenomena within certain human populations.
The island prefecture of Okinawa is the home to an indigenous population with the highest life expectancy in the world. The Okinawan diet – low in calories and high in micronutrients – constitutes another path to longevity that has long been championed by many scientists. They have found that rats and mice on calorie-restricted diets similar to that of the Okinawans have remarkable lifespan extensions.
Chen began her search for the secrets behind the Okinawan diet at the molecular level. Animals consume carbohydrates to drive cellular respiration and produce energy. The respiration process is mainly conducted by mitochondria, the cell’s power plants. However, energy production also generates unavoidable byproducts, called reactive oxygen species (ROS). These are natural chemicals that have roles in normal cellular function, and can usually be dealt with by antioxidant systems of the cell. However, like anything in excess, too many ROS are harmful to the body. ROS build-up results in a slow accumulation of protein damages and oxidative stresses in the cells.
In a way, this accumulation as a result of stress is a cellular reflection of aging. This is the reason that antioxidants such as vitamins are such an important component of our daily nutrition—they reduce ROS chemicals. For a long time, biologists thought that by simply reducing food intake with a restrictive diet, you decrease ROS production and, in turn, oxidative stress. The idea was that this would slow down the process of aging. However, data emerged to contradict this simple explanation. Caloric restriction, instead of decreasing cellular respiration, accelerates it and generates more ROS.
“This long-term slight increase in ROS production from caloric restriction actually conditions cells to oxidative stress,” explains Chen. “Because cells are constantly stressed at a low level, their antioxidative systems are better able to deal with the stress in the long run.” In other words, having a diet of fewer calories throughout a lifetime helps train the body to fend off future damages that are inevitable with aging.
Damages associated with aging
There are three options available for a damaged cell: it could destroy itself by programmed death, fix itself, or try to prolong its own life however it can. The mechanisms associated with unconstrained cell survival often lead to one of the main causes of death in older populations: cancer. Cancerous tumors are uncontrollable growths of cells whose sole raison d’etre is to survive and propagate. Chen explained the process as being initiated by “cells that escape the fail-safes installed by their own molecular checkpoints,” thus giving rise to damaged tissues and, eventually, cancerous tumors.
The question remains: if aging is an inevitable process that can only be slowed down at best, is it possible to deal with the damage associated with aging more efficiently? Theoretically, if an organism could repair damage without inducing programmed cell death, it could also have a longer life and avoid cancer. The Dillin lab has been very interested in figuring out what molecules repair these cellular damages associated with aging.
Most proteins, once no longer needed, are broken apart in a huge complex called the proteasome, which acts like a trash compactor that destroys them and recycles some of their parts. The Dillin lab, following the discovery of DAF-16’s role in germline-related life extension, found that one of its functional effectors is a component of the proteasome. It turns out that this key component, called Rpn6, is required to protect the cells of the reproductive system from the aggregation of damaged proteins. Without Rpn6, these proteins are like a trash pile that impedes normal cellular functions. “When Rpn6 is genetically manipulated to be more highly present in the somatic tissues instead of germline cells,” explains Dillin, “we discovered that the worm tissues that are not part of reproduction can get rid of protein damages faster and the worm lives longer.”
This may be the main reason that DAF-16 is an indispensible gene for germline ablation to prolong life. Its normal activities in somatic tissues are to repair damages and ensure long-term stability of the cell. These functions were hindered by the presence of the germline precursor cells, probably due to some unknown factors they produce. So once those cells were removed, DAF-16, through Rpn6 and the proteasome, was allowed to provide extra protection for the worm’s neurons and intestines where it is highly expressed, thus slowing down aging.
Can immortality be achieved?
While animals have very diverse life expectancies, the failure of one biological system or another ultimately drives all creatures to the same fate. For mice, it seems to be their lungs (older mice ultimately succumb to respiratory problems). For humans, it seems to be our heart that usually gives out first. “When people say someone died of old age”, says Dillin, “they often refer to some type of heart failure, even in prematurely aged patients.” Finally, casting a shadow over every living being is the constant threat of cancer in various somatic tissues.
Then again, consider the immortal jellyfish Turritopsis. Clearly, it has evolved to have some balance of longevity and regeneration that sets it apart from nearly all other creatures. Of course, there is little evidence that other organisms can achieve a similarly extraordinary feat of eternal youth. Besides, putting the scientific definitions of aging and death aside, is the tiny jellyfish really cheating death if the process requires its extreme developmental regression and the replacement of almost all of its cells? Such questions are hard to answer definitively.
If all we wanted was to achieve Turritopsis-style immortality, then perhaps we have already done it. One of the most famous cancer cell lines that is used in biomedical research is the HeLa cell line, derived from Henrietta Lacks, who died over 60 years ago. Meanwhile, the culprits of her death, her cervical cancer cells, are still proliferating in laboratories around the world. In a way, her cells can live forever even if she herself did not.
While much effort has been spent trying to prolong life itself, it is also important to understand the quality of an extended life. Aging research is not only about lifespan, but also the mental and physical changes that accompany the aging process. Chen studies how metabolic changes accompanying different diets could determine the rate of aging, but notes the challenges associated with targeting a single metric of health. “The prevailing idea is when you study cancer, you try to kill cancer cells but then something else could get you, like cardiovascular disease,” she explains. “If you get rid of cardiovascular diseases, then the immune system could fail you.” Her hope is that targeting aging could mean targeting all of these diseases. On the other hand, Dillin and colleagues believe that Rpn6 and its associated proteasomal functions could be the key to expanding life, or at least combat cellular damages that cause age-associated disorders such as cancer and cardiovascular disease.
One day, we may be able to apply what we know about worms and mice to treating human diseases and extending our lives by decades. However, for now the dream of living forever is only possible in legends—and even then neverending life is not without its drawbacks. After all, Tithonus had to live his eternal life as an old man because he forgot to ask for eternal youth. In the meantime, we can take comfort in knowing that the work of scientists at UC Berkeley and around the world may allow us to cheat death for a little longer. Perhaps even more importantly, they may also teach us how to make the most out of the time that we’ve got.