Secrets of Longevity: New Evidence from Rockfish
A genetic analysis of long-lived species of rockfish has led to fresh insights into human longevity, and a previously unappreciated pathway governing lifespan.
A new study of longevity in rockfish, which includes some species that live more than 200 years and others that live fewer than a dozen, identifies a set of genes controlling their aging process that has led to the discovery of a previously unappreciated group of genes associated with extended lifespan in humans. The research, which compared the genetics of long-lived and short-lived rockfish species, led to three especially significant findings:
- Longevity in rockfish is controlled by the same pathways that promote longevity in humans.
- Individual genes are less important to longevity than networks of longevity genes working together.
- A previously unappreciated metabolic mechanism governing “flavonoid metabolism” is an important contributor to longevity in both the longest-lived rockfish and humans.
Understanding why some humans live longer than others has long been complicated by the fact that there are millions of tiny genetic variations, called single nucleotide polymorphisms, or SNPs, between any two people. These single-letter changes in DNA sequence (written as G, T, C, and A, corresponding to the nucleotide bases guanine, thymine, cytosine and adenine) are so common that they make discovering which changes affect longevity (by studying centenarians, for instance) difficult. The use of rockfish to understand the genetics underlying longevity, and then the application of these findings to identify human genes controlling aging, is a clever approach to the research, which aims to find cures for diseases such as cancer, Alzheimer’s, and heart disease, for which the greatest risk factor is age itself.
“The core genetics of life are, in general, very well conserved across species,” explained Stephen Treaster, a research fellow in genetics at Harvard Medical School and Boston Children’s Hospital who led the study. “And when we look at lifespan, in particular, the interventions that we know affect longevity and aging in some model organisms also work in other, very diverse models.” Caloric restriction, for instance, extends lifespan in fruit flies, nematodes, and mice, “and even acts through the same gene,” he said in an interview. “And so, there is good evidence that the core regulators of these fundamental traits are well conserved across the tree of life.”
Most aging research to date has focused on extending the lifespan of such short-lived model organisms. But tweaking the lifespan of short-lived animals may not be an optimal approach—after all, says Treaster, “evolution already knows how to modulate longevity.” Why try to reinvent the genetics of extended lifespan, he asks, when instead it is possible to study the longest-lived organisms and figure out what genes are responsible for their long lives? Rockfish are an especially good subject of study because while some species live more than 200 years, others will develop, reproduce, and die during the course of just 11 years.
Treaster and associate professor of genetics Matthew Harris, senior author of the Science paper describing rockfish longevity, focused their studies on only the longest- and shortest-lived rockfish species, ignoring those with intermediate lifespans. Because rockfish first appeared recently in evolutionary terms, relatively few differences have evolved among the different species. Longevity, which appears to have been under strong selective pressure in some species, appears to be an exception. That makes the genetic differences among the long-lived and short-lived rockfish more likely to be significant in aging.
Prior genetic analyses of these fish, which live on the sea bottom where they hide under rocks, assumed that the long-lived species were a recent evolutionary change from a short-lived ancestor. But Treaster and his international collaborators discovered the opposite is true: rockfish became long-lived shortly after they first appeared, about 8 million years ago. From this ancestral, long-lived state, some species have recently evolved to become short-lived. This evolutionary strategy accelerates maturation to reproductive age and enhances survival of species living in environments with lots of predation or disease, where having offspring at a young age is an advantage. (In general, species that mature rapidly tend to have shorter lifespans, while those that mature at a later age generally live longer.)
Knowing the direction of the evolution in rockfish longevity—toward a shorter lifespan—guided the researchers to look for recent genetic changes in the short-lived species, and then to examine the variants of these same genes in long-lived species. These would be the genes that regulate extended lifespan, they reasoned. And that is what they found.
(Had they focused on recent changes to genes in the longest-lived rockfish, they would have discovered only genetic refinements that extend longevity in older fish, such as genes that suppress cancer and other diseases of old age, rather than the key genetic regulators of lifespan. The researchers did, in fact, find such genes in long-lived species, but note that these evolved independently and differently across various long-lived species, indicating that they were not the shared, master regulators of aging.)
Two major metabolic systems regulate lifespan in rockfish, the researchers found. One governs the insulin-signaling pathway that prior research has shown plays a major role in regulating the lifespan of many different animals. Finding that this pathway was a master regulator of rockfish longevity, too, was therefore an important validation of their research approach.
But they also uncovered a previously unappreciated “flavonoid metabolism” pathway that regulates rockfish lifespan. The genetic variants associated with long life in rockfish, they found, are significantly correlated with the analogous variants present in the top one percent of longest-lived humans.
Despite the name, the flavonoid metabolism pathway does not respond only to flavonoids, plant metabolites found in small quantities in the human diet. “The term is really a misnomer,” says Treaster. While the genes involved in this pathway do mediate the human response to plant flavonoids—many of which can either speed or slow aging—the flavonoid metabolism pathway’s internal function, he explains, is to regulate “neurotransmitters and the steroid hormones that are very much involved in the timing of sexual maturation.” This makes sense, he adds, since (as noted) long life is thought to arise principally as a side effect of delayed maturation, which can evolve in species that have no predators, susceptibilities to disease, or other selective pressures that would make early reproduction advantageous.
When Treaster, Harris, and their collaborators compared the pathways that confer long life on rockfish to variants of the analogous genes in long-lived humans they found something remarkable: changes in the flavonoid metabolism pathway were associated with human survival to extreme ages. Given the genetic distance between humans and rockfish, which last shared a common ancestor more than 400 million years ago, this result underscores the conservation of these core longevity mechanisms. The evolution of rockfish longevity, and survival to the 99th percentile in human populations, both lean on the same pathway. To make this comparison, they used a genome-wide association study (GWAS) of human longevity to identify single-letter DNA changes associated with long life. (A GWAS examines the whole genome of individuals, looking for genetic variants associated with a trait, such as longevity or susceptibility to a particular disease.)
One of the most interesting conclusions of the study is that single genes are less important to longevity than are networks of genes interacting to extend lifespan. When the researchers ranked rockfish and human gene variants according to their association with longevity, “no individual gene produced a blazingly strong signal. There was no silver bullet gene” that slowed aging. Instead, says Treaster, “We got this blazing signal at the set level. So, we think that longevity is leaning on this whole system, this network, not on any individual specific gene, at any given moment.”
Treaster is now modifying the longevity networks in zebrafish that govern flavonoid and insulin signaling, guided by the variation in rockfish and humans, to see if that will extend the lifespan of these unrelated fish. His goal: figuring out how to prevent, or at least delay, the common human diseases of old age.