We may find the secret to preventing cancer from elephants and blue whales

Cancer is essentially a disease caused by gene mutations. Specific mutations can cause cells to lose normal growth and division control, forming cancer cells. Every time a cell divides, there is a risk of mutation. In theory, the larger the animal, the more cells it has in its body and the more times the cells divide, so the chance of mutation should be higher. However, elephants, which are several times larger than humans, are not so prone to cancer. Why is this?

Part 1

TP53 - the guardian of the genome

The paradox — that cancer incidence appears to have nothing to do with the number of cells in an organism — was first discovered by epidemiologist Richard Peto in the 1970s and is known as Peto's paradox.

Schematic diagram of Peto's paradox: As expected, there is a linear relationship between cancer incidence and body size (orange line); in fact, there is no relationship between cancer incidence and body size (blue line)

(Image source: Reference [9])

Scientists have explained the longevity of elephants from a genetic perspective. In their study of elephant genes, scientists found that elephants have up to 20 copies of the TP53 gene, while humans and most other animals only have one copy of the TP53 gene.

The p53 protein encoded by the TP53 gene plays a vital role in cells and is known as the "guardian of the genome." The p53 protein "monitors" the cell's DNA at all times to ensure that no errors occur during cell division. It is mainly responsible for the following three tasks:

1. When the DNA of cells is damaged, the p53 protein prevents these cells from dividing and activates other genes to repair the DNA damage.

2. If DNA damage cannot be repaired immediately, p53 can pause the cell cycle, giving cells more time to repair the damage.

3. If the DNA damage is too severe to be repaired, the p53 protein will trigger the cell's self-destruction program - apoptosis, preventing the damaged cells from continuing to grow and divide, thereby preventing the occurrence of cancer.

Structure of p53 protein

(Image source: wikimedia)

Therefore, the multiple copies of the TP53 gene in elephants may enable them to have stronger DNA damage repair and cell apoptosis mechanisms, which may be an important factor in the low incidence of cancer in elephants. This mechanism is scientifically known as "enhanced tumor suppression."

Part 2

The extra TP53 gene in elephants may not be for longevity

Recently, a report published in the journal Trends in Ecology and Evolution explained further reasons why elephants are less susceptible to cancer. The authors proposed a hypothesis that the location of elephants' testicles may be related to the presence of multiple copies of the TP53 gene complex in their bodies.

Generally speaking, mammals need an environment 2-4 degrees Celsius lower than body temperature for sperm production. For example, the core body temperature of mice is 36.6 degrees Celsius, while the testicle temperature is 34 degrees Celsius, which is why the testicles of many mammals are in the scrotum outside the body.

However, elephants' testicles are located inside their bodies and their temperature is close to body temperature. Studies have shown that sperm production efficiency is greatly reduced in a slightly higher temperature environment, and even causes gene mutations, so this higher body temperature may have a negative impact on sperm quality.

The increase in the number of TP53 genes in elephants may not be due to selective evolution against cancer in the body (i.e., non-germ cells), but may be to protect reproductive cells - sperm. It is precisely because of this high temperature environment that may cause DNA damage, which stimulates the multiple replication of TP53 genes in elephants, thereby preventing the damaged cells from dividing and spreading.

Infrared thermal imaging of a baby elephant. The arrow shows the location of the testicles.

(Image source: Reference [2])

On the African grasslands, elephants experience long periods of sunlight, which raises their skin temperature. At the same time, the metabolism in the elephant's body also generates heat. For elephants weighing several tons, muscle activity (such as walking slowly or uphill) will generate heat. The temperature of their testicles may be consistent with the core temperature of the body, about 36-37 degrees Celsius.

The rationale for this assumption is that, due to cell turnover and replacement, the selection pressure on germline mutations is greater than that on somatic mutations. This means that mutations in germline cells are more likely to affect the evolution of an individual because these mutations can be passed on to offspring, whereas somatic mutations cannot be passed on.

In other words, the increase in the number of TP53 genes in elephants is to protect reproductive cells, and the anti-cancer effect may be just a side benefit.

Part 3

Longevity sometimes requires sacrifice

Whales are also large and long-lived animals, but unlike elephants, they only have one copy of the TP53 gene. So what is the reason for their longevity?

The bowhead whale (Balaena mysticetus) is a marine mammal belonging to the family of right whales that lives in cold Arctic and sub-Arctic waters. The bowhead whale is recorded as the longest-lived whale known, with a lifespan of more than 211 years, far exceeding the average lifespan of other whales, which is about 60 years.

The longevity of bowhead whales is largely due to a series of unique biological mechanisms in their bodies, which help them resist cancer, immune aging, cardiovascular and cerebrovascular diseases, metabolic diseases and neurodegenerative diseases. In particular, bowhead whales have demonstrated very effective anti-tumor mechanisms in preventing cancer.

Bowhead whale skeleton

(Image source: wikimedia)

A research team from the University at Buffalo, State University of New York, conducted an in-depth study of factors affecting the life span of bowhead whales. They found that about 4-5 million years ago, bowhead whales and right whales diverged into two different species, and bowhead whales formed a unique genome during evolution. This special genome encodes a species-specific reverse transcriptase called the cyclin-dependent kinase inhibitor gene (CDKN2C).

This gene set is highly expressed in the tissues of bowhead whales, and by slowing down the rate at which cells divide, each cell has more time to repair any damage it has sustained. This allows the cell to produce more cells with the same repair gene, thus reducing the risk of cancer. This unique genetic trait may be one of the key factors in the longevity of bowhead whales.

However, this mechanism of fighting cancer and increasing lifespan has a negative impact on the fertility of male bowhead whales.

The presence of the CDKN2C gene causes the testicles of male bowhead whales to shrink, thus affecting sperm production. In absolute terms, the testicles of bowhead whales weigh up to 200 kilograms, which is undoubtedly huge compared to ordinary human males. However, if compared with the testicles of their close relatives, right whales (the latter can reach 1,000 kilograms, which is five times that of bowhead whales), the testicles of bowhead whales appear very small.

In the process of evolution, bowhead whales have obviously chosen a survival strategy of longer life, even if it means that their testicles will become smaller and their fertility will be affected. Millions of years of evolutionary selection have allowed bowhead whales to live to more than 200 years old, which also proves the diversity of life and the diversity of survival strategies.

Bowhead whale

(Image source: wikimedia)

Part 4

Other Animals' Secrets to Longevity

There are indeed many creatures in the animal kingdom with quite long lifespans, and their longevity mechanisms are different, providing valuable reference materials for biologists' scientific research.

Naked mole rats are mammals that weigh only 35 grams on average, but can live up to 35 years, a longevity that is very rare for smaller rodents. After long-term studies on naked mole rats, scientists found that their mortality rate and risk of cancer do not increase with age.

This phenomenon can be attributed in part to the inhibitory mechanisms they establish early on. They have a unique protein, pALTINK4a/b, which plays an important role in preventing cell overgrowth and cancer formation in the presence of high molecular weight hyaluronan (HMW-HA), which can extend their lifespan.

Little brown bats, despite their small size, have a very long lifespan. This is related to the telomere dynamics and repair mechanisms of their growth factor-related genes. These repair mechanisms can effectively prevent aging-related DNA damage, thus helping to extend the lifespan of little brown bats.

Greenland sharks (Somniosus microcephalus) can live up to 400 years, and possibly even more than 500 years. They live in cold, deep-sea environments, which may contribute to their longevity. The metabolic rate of an organism is often related to the temperature of the environment: the lower the temperature, the slower the metabolic rate. Therefore, the Greenland shark's low metabolic rate may help reduce wear and tear on its body and may contribute to its longevity.

The longevity of these organisms provides valuable insights for scientists studying the mechanisms of aging and strategies to extend lifespan.

Part.5

Conclusion

In the process of biological evolution, many "secrets" have been found to resist cancer and increase lifespan. These longevity mechanisms are providing references for scientists to further explore the genetic codes of organisms. Perhaps in the near future, we will have more weapons to resist disease and aging.

References:

1. Keane M, Semeiks J, Webb AE, et al. Insights into the evolution of longevity from the bowhead whale genome[J]. Cell reports, 2015, 10(1): 112-122.

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3. Vazquez JM, Kraft M, Lynch V J. A CDKN2C retroduplication in Bowhead whales is associated with the evolution of extremely long lifespans and alerted cell cycle dynamics[J]. bioRxiv, 2022.

4. Padariya M, Jooste ML, Hupp T, et al. The Elephant evolved p53 isoforms that escape mdm2-mediated repression and cancer[J]. Molecular biology and evolution, 2022, 39(7): msac149.

5. Sulak M, Fong L, Mika K, et al. TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants[J]. elife, 2016, 5: e11994.

6. Nunney L. The real war on cancer: the evolutionary dynamics of cancer suppression[J]. Evolutionary applications, 2013, 6(1): 11-19.

7. Abegglen LM, Caulin AF, Chan A, et al. Potential mechanisms for cancer resistance in elephants and comparative cellular response to DNA damage in humans[J]. Jama, 2015, 314(17): 1850-1860.

8. Tejada-Martinez D, De Magalhães JP, Opazo J C. Positive selection and gene duplications in tumor suppressor genes reveal clues about how cetaceans resist cancer[J]. Proceedings of the Royal Society B, 2021, 288(1945): 20202592.

9. Tollis, M., Boddy, AM & Maley, CC Peto's Paradox: how has evolution solved the problem of cancer prevention?. BMC Biol 15, 60 (2017).

10. Tian, ​​Xiao, et al. “INK4 locus of the tumor-resistant rodent, the naked mole rat, expresses a functional p15/p16 hybrid isoform.” Proceedings of the National Academy of Sciences 112.4 (2015): 1053-1058.

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