inflammation & autoimmunity

TP53

The Role of Tumor Suppression in Aging & Longevity (TP53)

Written by Jasmine Foster, BSc, BEd on February 14th, 2020

When p53 is working correctly, it suppresses tumors; when it’s not, it opens the door to all sorts of cancers. What variants in TP53 have been associated with increased risk? Find out here.

What is Tumor Protein 53?

TP53 codes for tumor protein 53, or p53. For several years after its discovery, researchers tagged p53 as an oncogene — a gene prone to the types of mutations that can lead to cancer. However, p53 is actually a potent protein that works to “guard” the genome and prevent damaged and mutated cells from turning into cancer [R].

More specifically, p53 binds to specific sections of DNA, regulating gene expression and preventing damage and mutations. p53 also helps repair DNA that has already been damaged; its role in the DNA damage repair (DDR) system appears to be to stop the cell cycle (growth and division) to give the rest of the repair machinery time to work [R, R].

The Role of p53 in Aging & Longevity

As a tumor suppressor, p53’s most obvious link to longevity lies in the fact that cancer remains one of the deadliest diseases on Earth. People who live cancer-free are clearly more likely to live exceptionally long lives than those who develop cancer [R].

However, p53 is currently under investigation for a separate, but related, link to aging. In mice, overexpression of certain types of mutant p53 led to cancer resistance, but also to premature aging and death [R, R].

Researchers believe that DNA damage is among the primary drivers of aging. In response to DNA damage, p53 activates, stops the cell cycle, and allows the DNA damage repair (DDR) system to do its work. However, when the damage is beyond repair, the cell will either die (apoptosis) or simply stop reproducing indefinitely (senescence) [R].

Broadly speaking, the three possible outcomes of unrepaired DNA damage are apoptosis, senescence, or cancer. All three of these outcomes can significantly shorten a person’s remaining lifespan [R].

p53, of course, promotes DNA repair, which makes cancer and apoptosis less likely. However, it also stops the cell cycle and appears to make senescence more likely [R].

Variants in the p53 protein can tip the balance toward cancer, apoptosis, or senescence in response to DNA damage. This is at the root of p53’s complex relationship with longevity.

Mutant p53 and Aging

Certain p53 variants seem to be more likely to promote senescence and premature aging than others. In a study of 9219 Danish people, the ‘GG’ genotype at rs1042522 was associated with a lifespan approximately three years longer than the ‘CC’ genotype [R, R].

Researchers broadly agree that the ‘G’ allele confers greater longevity than the ‘C’ allele at this SNP. However, there is debate as to why this association exists. Currently, the hypothesis with the most support seems to be that the ‘G’ allele decreases apoptosis and increases cell cycle arrest (which would make cancer less likely); some researchers posit that this change allows for increased survival rates in people suffering from many types of disease [R].

Furthermore, people with the ‘CC’ genotype responded better to chemotherapy than those with the ‘G’ allele in a study of lung cancer patients. The decrease in apoptosis due to variant p53 may have helped the patients’ healthy tissues survive the stress of chemotherapy [R].

One SNP, rs1042522, has been associated with a three-year difference in life expectancy; researchers disagree as to the reason why.

The Cancer Connection

There have been a staggering number of studies connecting various p53 SNPs with cancer. For brevity, we will include lists below of the types of cancer connected to various SNPs, but we will not explore each type in detail. Remember: TP53 is just one factor that appears to affect the development of cancer. If you have risk alleles, you can still take steps to reduce cancer risk if you live a healthy lifestyle, eat a healthy diet, and follow your doctor’s recommendations.

Rs1042522

The ‘C’ allele is associated with:

Death from all causes and cancer [R]
Reduced general longevity [R, R, R]
Lower life expectancy [R]
General cancer [R, R, R, R, R]
Brain cancer [R, R, R, R, R]
Pituitary cancer [R]
Thyroid cancer [R]
Prostate cancer [R, R, R, R, R, R]
Penile cancer [R]
Lung cancer [R, R, R, R, R, R, R, R, R, R, R, R, R]
Breast cancer [R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R, R]
Cervical cancer [R, R, R, R, R, R, R, R, R, R, R]
Endometrial cancer [R, R, R]
Ovarian cancer [R, R]
Kidney cancer [R, R]
Bladder cancer [R, R, R, R, R]
Gallbladder and bile duct cancer [R, R, R, R]
Pancreatic cancer [R, R]
Mouth cancer [R]
Nasopharyngeal cancer [R, R]
Esophageal cancer [R, R, R]
Salivary gland cancer [R]
Head and neck cancer [R, R, R, R, R, R]
Eye cancer [R, R]
Bone cancer [R, R, R, R]
Lymph system cancer [R, R, R]
Leukemia [R, R, R, R, R, R, R, R, R, R, R]
Liver cancer [R, R, R, R, R, R, R, R]
Stomach cancer [R, R, R, R]
Skin cancer [R, R, R]
Colorectal cancer [R, R, R, R, R, R, R, R, R, R]
Effects of chemo [R]

This allele has also been associated with:

Heart attack [R]
Coronary heart disease [R, R, R, R, R]
Blood pressure [R]
Diabetes [R, R, R, R, R]
Alzheimer’s [R]
ALS [R]

Rs17878362

The insertion mutation (A2) is associated with:

General cancer [R, R, R]
Breast cancer [R, R, R, R, R, R, R, R]
Endometrial cancer [R]
Skin cancer [R]
Prostate cancer [R, R, R]
Colorectal cancer [R, R]
Pancreatic cancer [R]
Bladder cancer [R]

This allele has also been associated with diabetes [R].

Rs12951053

The ‘C’ allele is associated with:

Bone cancer [R]
Colorectal cancer [R]
Breast cancer [R, R, R, R]
Ovarian cancer [R, R]
Lung cancer [R, R]
Esophageal cancer [R, R]
Leukemia [R]
Cervical cancer [R]
Skin cancer [R]
Stomach cancer [R]

Rs1625895

The ‘C’ allele is associated with (the ‘T’ allele is protective from):

Lymph system cancer [R]
Skin cancer [R]
Colorectal cancer [R]
Lung cancer [R, R, R]
Breast cancer [R, R, R]
Brain cancer [R]
Endometrial cancer [R]

This allele has also been associated with:

Kidney transplant rejection [R]
Neural tube defects [R]

Rs2287498

The ‘T’ allele is associated with:

Laryngeal cancer [R]
Ovarian cancer [R, R]
Breast cancer [R]

Rs2078486

The ‘A’ allele is associated with:

Reduced general longevity [R]
Lung cancer [R]
Ovarian cancer [R]

Rs28934578

Breast cancer [R]
Li-Fraumeni syndrome, a genetic predisposition to cancer [R]

Your TP53 Results for Longevity

The following SNPs have been associated with longevity directly or indirectly through cancer. Again, it’s important to remember that while these mutations may affect disease risk in one way or another, they are not the only factor in cancer development! Lifestyle, diet, and exposure to harmful chemicals also play significant (and likely greater) roles. If you are concerned about your results, talk to your doctor about prevention strategies that may be right for you.

SNP Table

variant	genotype	frequency	risk allele
rs1042522
rs17878362
rs12951053
rs1625895
rs2287498
rs2078468
rs28934578

SNP Summary and Table

TP53 rs1042522

‘G’ = Associated with longer lifespan (about three years longer for ‘GG’ than ‘CC’)
‘C’ = Associated with average lifespan

TP53 rs17878362

‘A1’ = Not associated with cancer
‘A2’ = Associated with several cancers

TP53 rs12951053

‘A’ = Not associated with cancer
‘C’ = Associated with several cancers

TP53 rs1625895

‘C’ = Associated with some cancers
‘T’ = Appears protective against some cancers

TP53 rs2287498

‘C’ = Not associated with cancer
‘T’ = Associated with several cancers

TP53 rs2078468

‘G’ = Not associated with cancer
‘A’ = Associated with several cancers

TP53 rs28934578

‘C’ = Not associated with cancer
‘T’ = Rare mutation that may cause Li-Fraumeni syndrome & predisposition to cancer

Recommendations

Lifestyle

p53 appears to play a role in exercise and recovery; mice without functional p53 genes have reduced exercise capacity, endurance, and strength. Also in mice, exercise has been found to activate mitochondrial p53 and promote the repair of mitochondrial DNA [R, R].

There are no studies on the effect of exercise on p53 activity in humans. However, physical activity is broadly recognized to be a helpful strategy for cancer prevention. 3 hours of walking per week was significantly associated with reduced rates of breast cancer, for example [R].

Also in mice, chronic stress was found to hinder p53 activity and promote the development of tumors. Again, it is unknown whether stress reduces p53 in humans, but chronic stress is believed to broadly promote and worsen cancer. We recommend addressing sources of stress in your life, either by taking up a stress-busting hobby or seeking professional help [R, R, R].

Cigarette smoke and exposure to benzene and other pollutants have been associated with reduced p53 functionality, especially in those with detrimental mutations. We strongly recommend avoiding cigarettes and pollutants if at all possible [R, R, R, R].

Physical activity and stress reduction are among the best lifestyle choices for preventing cancer and increasing longevity. Exposure to cigarette smoke, benzene, and other pollutants is very harmful.

Diet

The complex relationship between diet and cancer has been the focus of many studies over several decades, and researchers have found interactions between food and p53.

Broadly speaking, people who eat a so-called “Western diet” rich in simple carbohydrates and processed foods are more likely than others to have mutant p53 in colon tumors [R].

Similarly, some researchers have suggested that a low-carb diet could inhibit DNA damage and tumor growth, but the evidence for this is limited to animal studies [R, R].

In terms of specific foods, cruciferous vegetables and other polyphenol-rich plants have shown the greatest promise. Cruciferous vegetables (which include broccoli, brussels sprouts, kale, and so on) contain a compound called phenethyl isothiocyanate (sulforaphane is another compound within the isothiocyanate group); this compound has been observed to preferentially kill cells containing harmful mutant forms of p53. This effect has not been directly observed in humans; however, the available data suggests that people who eat more cruciferous vegetables are less likely to develop cancer [R, R].

A new review of dietary polyphenols found that many common fruit and vegetable compounds increase p53 activity. The polyphenols reviewed included caffeic acid, acacetin, apigenin, quercetin, fisetin, curcumin, resveratrol, ellagic acid, and EGCG. Good sources of these polyphenols include coffee, many herbs and spices, onions, apples, berries, grapes, pomegranates, and red wine [R].

The simple carb-rich Western diet appears to be detrimental to p53 function. Among the best dietary options for p53, cancer, and longevity are cruciferous vegetables and antioxidant-rich plant foods.

Supplements

EGCG, one of the polyphenols that has been found to increase p53 activity in cells, also has anti-cancer activity in mice. EGCG is available as a supplement, and it is also abundant in green tea [R, R, R].

While the effect of green tea and EGCG on p53 has not been directly studied in humans, green tea consumption has been associated with a reduced rate of stroke, diabetes, and depression. Furthermore, in a Chinese study of over 9,000 elderly adults, green tea consumption was associated with reduced mortality rates [R, R].

Drugs

Half of all human cancers have mutated TP53; thus, researchers are currently developing drugs and experimental therapies that target p53 for cancer treatment. However, none are currently available [R].

Jasmine Foster

BSc, BEd

Jasmine received her BS from McGill University and her BEd from Vancouver Island University.

Jasmine loves helping people understand their brains and bodies, a passion that grew out of her dual background in biology and education. From the chem lab to the classroom, everyone has the right to learn and make informed decisions about their health.

Disclaimer

The information on this website has not been evaluated by the Food & Drug Administration or any other official medical body. This information is presented for educational purposes only, and may not be used to diagnose or treat any illness or disease.

Also keep in mind that the “Risk Score” presented in this post is based only on a select number of SNPs, and therefore only represents a small portion of your total risk as an individual. Furthermore, these analyses are based primarily on associational studies, which do not necessarily imply causation. Finally, many other (non-genetic) factors can also play a significant role in the development of a disease or health condition — therefore, carrying any of the risk-associated genotypes discussed in this post does not necessarily mean you are at increased risk of developing a major health condition.

Always consult your doctor before acting on any information or recommendations discussed in this post — especially if you are pregnant, nursing, taking medication, or have been officially diagnosed with a medical condition.

More inflammation & autoimmunity blogs

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Content

What is Tumor Protein 53? The Role of p53 in Aging & Longevity The Cancer Connection Your TP53 Results for Longevity

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