Longevity, Peto’s paradox & zombie genes

There is a conflict between longevity & cancer prevention.  If there is too little cell proliferation, the body cannot repair itself and stay ahead of the inevitable damage caused by living.  On the other hand, if there is too much cell proliferation, cancer can result.

Peto's paradox

Cancer is traditionally seen as an evolutionary process within the body, in which some cells gradually accumulate chance mutations that affect cell cycle control, eventually turning into tumor cells. By this reckoning, animals that live for a very long time and have a huge number of cells would seemingly have a high probability of getting cancer. Whales and elephants would be expected to die of cancer far more frequently than mice or humans. And yet they don’t. 

Image credit: modified from Evolutionary Biology: How elephants beat cancer. Gaughran et al., 2016.

The frequency of tumors, or of death by cancer, is about the same for mice, humans, elephants, and whales (or even lower for the largest mammals). This unexpected fact is known as Peto’s paradox. The fact that tumor prevalence doesn’t increase with size and lifespan indicates that tumorigenesis isn’t simply an inevitable consequence of uncontrollable mutation; instead, it’s controlled by molecular mechanisms that have been shaped by evolution. If elephants are resistant to cancer, they must have some molecular tricks to prevent it. Biologists who want to understand longevity and health have been working to understand those molecular tricks.

Elephants: p53 and zombie genes

Extra copies of p53

As you’ve already seen, the tumor suppressor p53 is critically important in preventing tumors. A human who inherits a single defective copy of p53 (a loss-of-function allele)  will have Li-Fraumeni syndrome, which is characterized by a greatly increased risk of cancer. On the other hand, elephants actually have extra copies of p53 in their genomes. While humans inherit one copy of the p53 gene from each parent, elephants have 20 different copies (or 40 copies in the diploid genome). The extra copies can have two important effects:

• If one copy is mutated, there are multiple backups. It’s unlikely that all those copies will become mutated.
• The different copies of p53 are at different loci, or places within the chromosomes. Each locus can evolve independently, so it’s possible that the different versions of p53 created by gene duplication (called paralogs) have acquired slightly different functions. 

It seems likely that the extra copies of the p53 genes in the elephant genome contribute to longevity and cancer resistance. In fact, laboratory mice that have been genetically altered to have extra copies of p53 have also displayed increased resistance to cancer.

The extra copies of the p53 gene result from gene duplication, in which segments of DNA get copied more than once during DNA replication. 

Zombie LIF genes

Elephants also have extra copies of another gene, called LIF. All mammals have a LIF gene, which is involved in controlling cell proliferation, but elephants have multiple copies due to gene duplication.

Most of these extra LIF copies are pseudogenes: nonfunctional remnants of genes that no longer get expressed. Pseudogenes are commonly found in the genomes of all kinds of organisms. They commonly result from the chance duplication of a region of DNA. If a complete gene is duplicated, the genome now has an extra copy, but if the extra copy is incomplete and nonfunctional, it is a pseudogene. 

The original LIF gene (in elephants and other mammals) contains multiple exons and introns, and not all of them are present in the elephant LIF pseudogenes. In addition, some of the pseudogenes lack the necessary control elements (such as transcription factor binding sites).

Image credit: Vazquez et al. A zombie gene in elephants Is Upregulated by TP53 to Induce Apoptosis in Response to DNA Damage.

However, one of the pseudogene copies of LIF apparently came back to life. Researchers found that this former pseudogene (called LIF6) is regulated by the tumor suppressor and transcription factor p53. When expressed, the LIF6 protein induces apoptosis in response to DNA damage. Thus, compared to most mammals, elephants have an elevated apoptosis response to DNA damage, which may be an important part of their escape from Peto’s paradox. They are quick to destroy cells that could potentially turn cancerous.

The researchers referred to LIF6 as a “zombie gene” because it apparently came back from the undead realm of pseudogenes. In fact, this may be a common mechanism for the evolution of “new” genes.

Bats are long-lived

According to Peto’s paradox, the surprising thing about elephants is that they rarely get cancer, despite their huge bodies and long lives. What’s not surprising is the long lifespan itself. Larger animals consistently live longer than small ones, with lifespan increasing predictably as a function of body mass. By this reasoning, bats turn out to be surprising in a different way: they lead much longer lives than do other mammals of the same size. Bats can live for decades, compared to a couple of years for a mouse.

While lifespan can generally be predicted according to body mass in mammals, the long lives of bats make them true outliers:

Image credit: Foley et al., Growing old, yet staying youg: The role of telomeres in bats’ exceptional longevity.

The "longevity quotient" in this diagram represents the deviation from the expected lifespan for a mammal of a given size. On average, mammals have a longevity quotient of 1. Bats are smaller than most mammals, but live far longer than would be predicted. This raises two related questions: How do they manage to live so long? And if they do live so long, how do they (apparently) avoid the expected additional burden of cancer?

You did some reading about bats at the beginning of the quarter. You learned (I hope) that bats have evolved to sustain the high metabolic rates required by flying, which means that there has been relatively rapid evolution in the genes related to oxidative phosphorylation (OX-PHOS) and related processes. A high rate of OX-PHOS results in a high rate of production of superoxide and other reactive oxygen species (ROS). Since these ROS can cause substantial DNA damage, the pathways connected to DNA repair have had to evolve along with the energy pathway genes. 

As it turns out, many of the rapidly-evolving genes in bats are connected to the cell cycle:

• p53: Tumor suppressor. The bat version of this gene contains a mutation in a region that controls where the protein is localized within the cell; this may affect its regulation.
• ATM: Works alongside p53 in the DNA damage response for both stopping the cell cycle and initiating the intrinsic apoptosis pathway.
• MDM2: Downregulates p53. Bats' mutated version of this gene may affect p53 regulation.
• BRCA: DNA repair; defects in this gene increase the probability of cancer.
• Telomere-related genes, with the result that bats maintain long telomeres throughout their lifetimes, which may contribute to their exceptional longevity.

The detailed effects of these genetic changes are not yet understood, but the end result is that bats are very good at protecting themselves from oxidative damage, repairing DNA, and preventing cancer, while experiencing reduced levels of inflammation in response to DNA damage or viral infection. 

By studying sets of genes connecting seemingly unrelated processes (energy metabolism, DNA repair, and immunity) in seemingly obscure groups of animals, biologists have uncovered mechanisms that are likely to have great relevance to human life. It would seem that we still have a lot to learn from bats, as well as from elephants.

Review

Terms & concepts

Numerous gene names are mentioned on this page; you don't need to memorize them all. Focus on the terms below:

• Gene duplication: An event in which an extra copy of a region DNA is produced in the genome. In many cases, gene duplication is caused by transposons or by errors in meiosis.
• Locus (singular) and loci (plural). A specific location on a chromosome. Often refers to a gene, but could also refer to any particular location, coding or not. In the human genome, there is one p53 locus, but in the elephant genome there are 20 p53 loci.
• p53
• Paralog: A gene that is a duplicate of another gene in the same genome; gene duplication creates paralogs. The paralogs may be identical when they first occur, but can evolve to become different from one another. Eukaryotic genomes are made up of multiple gene families, or groups of paralogous genes, generated by multiple gene duplication events over evolutionary time.
• Peto's paradox
• Pseudogene: A nonfunctioning duplicate copy (paralog) of another gene. A pseudogene may have a valid open reading frame (ORF), but fails to get expressed. The only way to tell if a sequence is a functioning gene or a pseudogene is to see if it gets transcribed (in other words, look for the mRNA).
• Zombie gene: A former psudogene that has become re-activated by a new mutation, causing it to be expressed again. (This isn't actually a widely used scientific term, but it's useful.)

Review questions

1. What genetic features contribute to the low rate of cancer in elephants?
2. What genetic features contribute to the low rate of cancer in bats?
3. What is the connection between high metabolic rate and DNA repair mechanisms?
4. What is the connection between telomere shortening and lifespan?
5. How could an increased rate of apoptosis potentially lengthen an animal's lifespan? How could it potentiall shorten an animal's lifespan?
6. How would you know if two genes are paralogs?
7. How would you know if an open reading frame is a pseudogene?

References & further reading

Peto's paradox

Peto’s Paradox: how has evolution solved the problem of cancer prevention? Tollis et al., 2017. BMC Biology.

Elephants

The ‘Zombie Gene’ That May Protect Elephants From Cancer. Zimmer, 2018, The New York Times. Clear and easy to read, with links to research articles.

Elephants Have a Secret Weapon Against Cancer. Yong, 2018. The Atlantic. News article; clear, interesting, and easy to read.

A Zombie LIF Gene in Elephants Is Upregulated by TP53 to Induce Apoptosis in Response to DNA Damage. Vazquez, 2018. Cell Reports. A technical research article; challenging, but clear and comprehensible.

Evolutionary Biology: How elephants beat cancer. Gaughran et al., 2016. ELife.  A news article related to the Sulak article listed below.

P53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants. Sulak et all, 2016. ELife. Original research article.

Bats

Growing old, yet staying young: The role of telomeres in bats’ exceptional longevity. Science Advances, 2018. From the abstract: "Understanding aging is a grand challenge in biology. Exceptionally long-lived animals have mechanisms that underpin extreme longevity.... We demonstrate how telomeres, telomerase, and DNA repair genes have contributed to the evolution of exceptional longevity in Myotis bats, advancing our understanding of healthy aging."

Longitudinal comparative transcriptomics reveals unique mechanisms underlying extended healthspan in bats. Huang et al., 2019. Nature Ecology & Evolution. Research article. The authors provide a detailed analysis of how gene expression changes over time in bats, and how these changes are connected to longevity. This is probably more than you want to know about the subject, but this article represents a powerful modern approach to biology.

The long lifespan of two bat species is correlated with resistance to protein oxidation and enhanced protein homeostasis. Salmon et al., 2009. This research article shows how oxidative damage, protein quality control, and longevity are interconnected.

Biological time

These cellular clocks help explain why elephants are bigger than mice. Nature, 2021. This easy-reading news article describes some recent research into why things happen more slowly in larger organisms.