Long-Lived Species (Why Solve Aging: Part 6)

Overview

Many animals live a very long time, even when closely related to much shorter-lived animals.  Not all animals even age at all -- that is, while they do eventually die, they don’t become less healthy over time or have an increasing mortality risk as they grow older.

This means that a.) it’s possible for an animal to live much longer than the human lifespan, even as long as centuries; and b.) lifespan is naturally selected, which implies there are genes that affect the rate of aging.  

If extreme long life can exist in the animal world, maybe some of the techniques animals use to live so long can be “borrowed” for human therapies.

Many of the exceptionally long-lived animals are cold-blooded, live in cold climates, and/or hibernate, indicating that low metabolic rate may be involved in aging. However, bats and birds are long-lived and have small bodies and high metabolic rates, indicating that they have some protective mechanisms against aging that might still be applicable to humans.

Longer-lived animals, as one might expect, also display less of the hallmarks of aging.  Many have more damage-resilient proteins, better DNA damage repair, or slower-shortening telomeres (the chromosomal “clocks” that run down as cells senesce.)  This is evidence that the hallmarks of aging are causal, and thus that reversing them might extend life.

Bivalves

Some bivalve molluscs can live for centuries; the ocean quahog has a lifespan of 375 years and the freshwater pearl mussel lives 190 years, while other bivalves live just 2 years.  These long-lived species do not have increased mortality rates with age. They live in very cold temperatures and reduce their metabolic rates through hibernation, two factors associated with long life in other species as well.[9]

Sharks

The Greenland shark is the longest-lived vertebrate, with a maximum measured lifespan of 392 years.[19]  Like other aquatic long-lived animals, it is cold-blooded and lives in very cold temperatures, and adaptations to these conditions (such as slow growth and metabolism) may be relevant to its long life.[24]

Whales

The bowhead whale is the longest-lived mammal, with a maximum lifespan of 211 years. Like sharks and long-lived bivalves, they live in cold temperatures.

Bowhead whales have unique genetic characteristics related to their longevity. Genes under positive selection include ERCC1, which encodes a DNA repair protein, and UCP1, which encodes a mitochondrial protein for brown adipose tissue, involved in thermogenesis.[17] Like naked mole rats (another long-lived mammal species), bowhead whales have impaired thermogenesis. Thermogenesis, the metabolic production of heat to keep an animal warm, is energetically expensive and increases risk of cancer; reduced thermogenesis may contribute to longevity.

A number of transcriptional abnormalities in bowhead whales have also been discovered that might contribute to their longevity.  Bowhead whales have diminished GRB14 expression in the liver compared to other mammals; when this gene is knocked down in mice, insulin sensitivity is increased.  The genetic modifications in bowhead whales may represent adaptations to a high-lipid diet and the large fat stores needed to survive in the Arctic.[18

Other whales are also long-lived: Narwhals can live to be 115 years[20] and fin whales can live to be 135.[21]  Whales have specific adaptations for deep dives, which cause oxidative stress because the body is temporarily deprived of oxygen; whales show alterations in glutathione metabolism, and increased glutathione levels when subject to oxidative stress, which may be an adaptation to counteract hypoxia-induced tissue stress. These same adaptations might help whales resist aging-related stress.[22]

Rockfish

Rockfish (genus Sebastes), another slow-growing, cold-water organism, can live to be over 200 years old.[6]  They continue to produce eggs throughout their lifetimes.[11]

Turtles

The longest-lived turtle was a giant tortoise (Geochelone gigantea) which lived over 150 years. Long life is widespread among turtle species; of 8 families of turtles, half had species that lived over 50 years.  There is “little evidence” that turtles have declining health as they age; they do not even become infertile, continuing to lay eggs until they die.[2]  Leatherback turtle telomeres do not shorten.[12]

Freshwater turtles, like whales, are air-breathing animals that have evolved to survive periods of oxygen deprivation while diving underwater.  Turtles maintain high levels of antioxidants such as superoxide dismutase, to survive the oxidative stress of returning above water after hours of anoxia. When anoxia begins, turtle brains experience a sharp rise in the inhibitory neurotransmitter GABA, which prevents the spike in excitatory neurotransmitters that kills neurons in response to oxidative stress.[23]

Birds

Birds live about 3x longer than non-flying warm-blooded animals of similar size. Cockatoos can live to be 65 and larger birds, such as the Andean condor, can live to 75. Longer-lived birds have slower-shortening telomeres, and one long-lived bird (the storm petrel) does not exhibit telomere shortening at all.  Long-lived birds also show more protein resistance to experimentally induced oxidative stress.[14] Some seabirds, such as the California gull, experience no reproductive senescence -- they remain fertile their whole lives.[15]

Elephants

Elephants live up to 70 years. They have 19 extra copies of the TP53 tumor suppressor gene, which causes apoptosis (programmed cell death for defective cells) and, indeed, they undergo more apoptosis than their close relatives, killing DNA-damaged cells before they become cancerous.[16]  “Peto’s paradox” is the observation that very large animals should have a higher risk of cancer (since they have more cells, and thus more opportunities for a tumor to start), but in fact large animals rarely get cancer. Elephants resolve this “paradox” through their unusually strong apoptotic protections against cancer.

Bats

Bats live over 3x longer than nonflying mammals of equal size; in Siberia, Brandt’s bat, the longest-lived bat species, can survive to be 41 years old.[13]  This may be because they spend a long time hibernating; bats that hibernate live longer than bats that don’t.[4] Bats have better proteostasis (protein resilience to oxidative stress) than mice.  Bat proteins are more stable to radiation damage and bats have less ubiquitination or proteosome activity (mechanisms for getting rid of defective proteins), indicating that bat proteins are exceptionally stable.[7]  The growth hormone receptor is mutated in bats, leading to less GH-IGF signaling, a genetic pathway also associated with longevity and cancer resistance in mice, worms, flies, and humans.[16]

Naked Mole Rats

Naked mole rats live in captivity for more than 28.3 years, ~9 times longer than similar-sized mice. They do not show signs of physical deterioration with age, never spontaneously develop cancer, breeding females remain fertile their whole lives, and mortality rates do not accelerate with age.  Naked mole rat blood vessels remain elastic in old age, their basal metabolic rates do not change, their bone mineral content does not decline, they do not become less sensitive to insulin, and they do not lose cartilage.[3]

Naked mole rats have a high-molecular-weight version of the connective tissue component hyaluronan, and this is what causes their complete resistance to cancer; if you alter the hyaluronan gene, naked mole rats can be given cancer.  Naked mole rats also have higher fidelity of protein translation than other mammals, i.e. they are less likely to produce defective proteins. A genetic study of naked mole rats also found an alteration in the thermogenesis protein UCP1 (naked mole rats are unique among mammals for being cold-blooded), alterations in melatonin receptors, and alterations in telomere maintenance genes.[8]

Comparative Studies

Longer-lived birds and mammals have slower-shrinking telomeres than shorter-lived animals.[1]

Longer-lived mammals (like cows and horses) have less mitochondrial DNA damage than shorter-lived mammals (like mice and rats.)[2]  In paired comparisons between long-lived and short-lived mammals, bats, and marsupials, the long-lived animals had higher levels of protein chaperones and more autophagy, indicating that they’re better at preserving proteins from misfolding and eliminating defective proteins.[10]

Conclusion: Protective Mechanisms

Long-lived animals have a number of protective mechanisms against aging. Many have no thermogenesis (being cold-blooded, like bivalves, rockfish, sharks, turtles, and naked mole rats), impaired thermogenesis (like bowhead whales), or go through hibernation periods with less thermogenesis (like bats).  The critical gene in thermogenesis, UCP1, is shared with humans and mutated in several long-lived species. Resistance to anoxic stress seems to contribute to longevity in whales and turtles, via large amounts of antioxidant activity. Some species have unique protective mechanisms, such as elephants’ extra copies of TP53, naked mole rats’ ultra-strong version of hyaluronan, bats’ absence of growth hormone, or bowhead whales’ better insulin sensitivity and improved DNA repair. Finding drugs or therapies that mimic these life-prolonging adaptations might enable us to apply them to humans.

References

[1]Haussmann, Mark F., et al. "Telomeres shorten more slowly in long-lived birds and mammals than in short–lived ones." Proceedings of the Royal Society of London B: Biological Sciences 270.1522 (2003): 1387-1392.

[2]Gibbons, J. Whitfield. "Why do turtles live so long?." BioScience 37.4 (1987): 262-269.

[3]Buffenstein, Rochelle. "Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species." Journal of Comparative Physiology B 178.4 (2008): 439-445.

[4]Austad, Steven N., and Kathleen E. Fischer. "Mammalian aging, metabolism, and ecology: evidence from the bats and marsupials." Journal of Gerontology 46.2 (1991): B47-B53.

[5]Barja, Gustavo, and AsunciÓn Herrero. "Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals." The FASEB Journal 14.2 (2000): 312-318.

[6]Guerin, John C. "Emerging Area of Aging Research: Long‐Lived Animals with “Negligible Senescence”." Annals of the New York Academy of Sciences 1019.1 (2004): 518-520.

[7]Salmon, Adam B., et al. "The long lifespan of two bat species is correlated with resistance to protein oxidation and enhanced protein homeostasis." The FASEB Journal 23.7 (2009): 2317-2326.

[8]Gorbunova, Vera, et al. "Comparative genetics of longevity and cancer: insights from long-lived rodents." Nature Reviews Genetics 15.8 (2014): 531.

[9]Philipp, Eva ER, and Doris Abele. "Masters of longevity: lessons from long-lived bivalves–a mini-review." Gerontology56.1 (2010): 55-65.

[10]Pride, Harrison, et al. "Long-lived species have improved proteostasis compared to phylogenetically-related shorter-lived species." Biochemical and biophysical research communications 457.4 (2015): 669-675.

[11]de Bruin, Jan-Peter, et al. "Ovarian aging in two species of long-lived rockfish, Sebastes aleutianus and S. alutus." Biology of reproduction 71.3 (2004): 1036-1042.

[12]Plot, Virginie, et al. "Telomeres, age and reproduction in a long-lived reptile." PloS one 7.7 (2012): e40855.

[13]Podlutsky, Andrej J., et al. "A new field record for bat longevity." The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 60.11 (2005): 1366-1368.

[14]Munshi-South, Jason, and Gerald S. Wilkinson. "Bats and birds: exceptional longevity despite high metabolic rates." Ageing research reviews 9.1 (2010): 12-19.

[15]Holmes, D. J., R. Flückiger, and S. N. Austad. "Comparative biology of aging in birds: an update." Experimental gerontology 36.4-6 (2001): 869-883.

[16]Seluanov, Andrei, et al. "Mechanisms of cancer resistance in long-lived mammals." Nature Reviews Cancer (2018): 1.

[17]Keane, Michael, et al. "Insights into the evolution of longevity from the bowhead whale genome." Cell reports 10.1 (2015): 112-122.

[18]Seim, Inge, et al. "The transcriptome of the bowhead whale Balaena mysticetus reveals adaptations of the longest-lived mammal." Aging (Albany NY) 6.10 (2014): 879.

[19]Nielsen, Julius, et al. "Eye lens radiocarbon reveals centuries of longevity in the Greenland shark (Somniosus microcephalus)." Science 353.6300 (2016): 702-704.

[20]Garde, Eva, et al. "Age-specific growth and remarkable longevity in narwhals (Monodon monoceros) from West Greenland as estimated by aspartic acid racemization." Journal of Mammalogy 88.1 (2007): 49-58.

[21]Ditte Haue. "Finhvalen var mindst 135 år gammel | Nyheder | DR". Dr.dk. Retrieved 13 May 2013

[22]Yim, Hyung-Soon, et al. "Minke whale genome and aquatic adaptation in cetaceans." Nature genetics 46.1 (2014): 88.

[23]Lutz, Peter L., Howard M. Prentice, and Sarah L. Milton. "Is turtle longevity linked to enhanced mechanisms for surviving brain anoxia and reoxygenation?." Experimental gerontology38.7 (2003): 797-800.

[24]Costantini, David, et al. "The Greenland shark: A new challenge for the oxidative stress theory of ageing?." Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology 203 (2017): 227-232.