Short RNAs in Stress and Longevity

My latest eBriefing for the New York Academy of Sciences covers a day-long May 12 meeting on "Short RNAs in Stress and Longevity." (The web publication was delayed by redesign and reorganization disruptions at the academy).

The sponsor, the Non-coding RNA Biology Discussion Group, used to call itself the RNA Interference Discussion Group. Its new name more accurately reflects the diverse regulatory and other roles of short RNAs. Many of these roles are far from being completely understood, and this meeting touched on several of them.

The combination of stress and longevity may seem like an odd pairing. But to the extent that many organisms have a built-in, switchable longevity program, stresses like starvation, which make living longer more attractive than reproducing, can activate it. The stress response is an entire field of its own, and stresses like heat shock are well known to produce major shifts in gene expression, inducing production of proteins like chaperones that help cells cope.

Frank Slack of Yale University and Ramanjulu Sunkar of Oklahoma State University explored two fields where researchers have extensively studied gene regulation by traditional protein-based mechanisms. For longevity in the worm C. elegans and for stress responses in plants, respectively, they saw the effects of naturally-occurring short RNAs (microRNAs and their plant relatives), and changed these responses by manipulating the short RNA levels. As in other fields, these studies are revealing a critical layer of gene regulation that has been overlooked until quite recently.

Germano Cecere works in the lab of Alla Grishok of Columbia University, who had found that short RNAs can regulate not just messenger RNA translation and degradation, but also its initial transcription from DNA. To find new examples, Cecere searched for short RNAs that are involved with chromatin remodeling, and identified many that play a role in stress and longevity.

Cells under stress often develop specialized complexes of proteins and RNA, known as stress granules, which may host some of the regulatory reactions or store low-priority messenger RNA. Anthony Leung of Phil Sharp's lab at MIT described how a particular polymer known for its role in DNA processes might act as a scaffold for these granules or even help regulate their activity.

Irina Groisman of the André Lwoff Institute dissected protein complexes that associate with the poly-adenylated tails found in mature messenger RNA. These complexes enforce the tradeoff between cellular senescence, which is related to longevity, and cancer.

Beyond the regulatory sequences that typically contain twenty-something bases, larger RNA can also process information on its own. Evgeny Nudler of NYU, who had identified riboswitches that respond to metabolites, described a different 600-nucleotide-long RNA that is the temperature-sensing element in the heat-shock response. This RNA sensor binds with the translational elongation factor eEF1A (which can also interact with non-heat stresses) to generate the response.

As this breathless summary hints, it's a challenge to combine such disparate topics into a coherent writeup. In this case, with just six talks, I gave up on aligning the talks into common themes and simply summarized each one separately. This diversity shows how wide open the field of RNA remains, going far beyond its traditional functions as messenger RNA, transfer RNA, and ribosomal RNA.

Medicine Nobel

The 2009 Nobel Prize in Physiology or Medicine was awarded to Elizabeth Blackburn, Carol Greider and Jack Szostak, for their unraveling the special role of the ends of chromosomes, and how they are maintained. The tips of the chromosomes, called telomeres, help ensure the eventual senescence of cells--a process that breaks down in cancers.

In the early days of DNA, as scientists clarified the molecular mechanisms of its replication, they realized that the ordinary step-by-step copying process would not function all the way to the end of the chain. Over time, it seemed, the DNA would get shorter and shorter, progressively infringing on coding sequences near the end of the chain. Szostak and Blackburn discovered that the ends contained a repeated six-base sequence, CCCCAA. A cap of proteins bind to this sequence and protects the tips--Blackburn has likened them to the plastic tips that keep the ends of shoelaces from fraying. Blackburn and her then student Greider discovered the enzyme, telomerase, that recognizes and extends this sequence to prevent continued erosion of the genetic information during division.

Only a few cells normally produce telomerase, however. It had been discovered by Leonard Hayflick that many cells, grown in culture, only divide a fixed number of times--now known as the "Hayflick limit," after which they enter an extended period of senescence. This observation suggested a built-in program for aging that might limit longevity even in multicellular organisms. Researchers quickly realized that the shortening of the telomere during DNA replication provided a natural mechanism for this limit to the number of cell divisions.

Some ordinary cells, like those that lead to sperm and eggs, naturally make the telomerase that restores the telomeres. The enzyme is also produced by many cancer cells, which is one of the reasons that they are able to evade the usual limitations on cell division.

The role of telomerase in preventing cellular senescence suggested to many researchers that the enzyme might also arrest aging in complex creatures like ourselves. The biotech company, Geron, for example, was founded in 1992 in the hopes of exploiting telomerase against aging. Of course one of the dangers of such an approach would be that it might remove protections against cancers. On the other hand, researchers have sought drugs that suppress telomerase as potential anti-cancer agents.

The reality of aging is, not surprisingly, more complicated, and telomerase has not proven to act like the mythical fountain of youth. Geron has moved on to other pursuits, notably stem cells. The current wave of excitement about anti-aging centers on completely different drugs aimed at activating the same molecular pathways as severe caloric restriction, which has long been known to extend life even in mammals.

Even though telomeres and telomerase have not released us from aging, however, their discovery has clarified important aspects of cellular division and programmed senescence, and stimulated new approaches to drug development.

A very good book that discusses the Hayflick limit, telomeres, Geron, caloric restriction and much more is Stephen S. Hall's 2003 Merchants of Immortality.

A Program for Aging?

In the science section of today's New York Times, Nicholas Wade skillfully reviews progress toward drugs to extend human lifespan. As he notes, researchers have known for decades that severe caloric restriction extends the life of many animals. Beginning in the 1990s they realized that changing the action of even one gene, for example by mutation or drugs, can have a similar effect. I've written on incremental advances for Scientific American in 2004 and for The Scientistin 2005, but there has been steady progress before and since.

I do, however, question Wade's assertion that "Evolutionary biologists, the experts on the theory of aging, have strong reasons to suppose that human life span cannot be altered in any quick and easy way. But they have been confounded by experiments with small laboratory animals, like roundworms, fruit flies and mice." Although I'm sure some evolutionary biologists would be skeptical, others have devised coherent ways to understand how a reprogrammable lifespan could evolve.

The first thing to recognize is that immortality is perfectly normal, in the following sense: your cells are the surviving members of an unbroken line of succession going back billions of years. Sure, along the way, many individual animals died without offspring. Even in the animals that reproduced to pass on the torch, most cells died along with their bodies. But their sacrifice doesn't alter the overall continuity of life, any more than the billions of skin cells you lose each day.

So practically speaking, cellular processes are quite capable of self-renewal that makes organisms immortal. There's nothing inherent about death, in a properly self-maintained body. The idea that we just "wear out" after a while is an oversimplification, partly based on analogy with the flawed machines that we build. There is accumulating damage to the telomeres at the end of chromosomes and oxidative damage resulting from metabolism, but clearly there are ways to evade them.

Why then do our bodies die at all, to be replaced by new generations? This is where it gets interesting, and speculative. One reason could be that periodic sexual scrambling of our genetic material is important for evolutionary innovation. No doubt there's some truth to that, but asexual species also have a fixed, relatively short lifespan. Whatever the reason, it seems that there are benefits to building a new body from scratch. As Thomas Jefferson said, "a little rebellion, now and then, is a good thing."

But how much? How often should generations turn over? The optimum must be a tradeoff between the benefits of new bodies (whatever they may be) and the cost of making them, such as energy and nutrients. The growing offspring are also vulnerable to predators and harsh living conditions.

From this point of view, it hardly seems shocking that we would have ways of recalculating the tradeoff between reproduction and longevity, and there's lots of experimental support for this view. Think of the calorie-reduction effect: when resources are short, all sorts of animals live longer. It makes sense to conserve scarce resources and reproduce when times get better. The widely studied roundworm C. elegans even goes into a long-lived dormant state, something like the spores of some plants, when conditions are bad. Researchers have also found direct that reproducing causes changes that reduce lifespan. (It's not entirely a myth that your kids make you age prematurely--although they also make you young.)

What's particularly interesting is that the biochemical pathways that underlie these responses--the specific molecules and the ways they influence one another--have many common elements in creatures ranging from humans to worms and flies and even to single-celled yeast. Each of these species lives longer when food is drastically reduced, even though the specific ways in which they eventually die are completely different. (Few yeast die of heart attacks, for example.) This suggests to many researchers that there may be a "program" that modifies lifespan in response to environmental and reproductive conditions, and that that program has been adopted and adapted over hundreds of millions of years of evolution.

If so, the question is whether we can hack into this ancient program. And should we?