Biological exceptionalism: how two Italian sisters lived to be 100

IIn my endless email about COVID-19, a new article appeared analyzing the health of two Italian sisters who lived to a ripe old age.

The phenotypic characterization of the Cammalleri sisters, an example of exceptional longevity, by Calogero Caruso MD of the University of Palermo, Italy, and colleagues, is published inRejuvenation research.

Filippa was a 106-year-old semi-supercentenarian, born on December 12, 1911 and died on July 6, 2018. Her sister Diega, born on October 23, 1905 and died on June 15, 2019, was over one hundred years old, lived to be 113 years old. centenarians those who see their 100thbirthdays only 1 in 1,000 reaches 110. Only 27 supercentenarians are known in the world.

An article about The New YorkerWas Jeanne Calment the Oldest Person Who Ever Lived or a Fraud? she told the story of the famous French woman who died in 1997, allegedly at the age of 122. But as historical inconsistencies emerged, investigators discovered the dead woman may have been a daughter in disguise. Lauren Collins wrote, Jeanne Calment was an accidental icon, her celebrity the result of a form of passivity. For one hundred and twenty-two years, five months and fourteen days, Calment managed not to die.

But Filippa and Diega Cammalleri were real and studied.

The anti-aging industry is one for all

The researchers gave the sisters a detailed questionnaire in July 2017, took all kinds of measurements, and did limited blood and genetic tests. What their findings reveal about their physiology runs counter to what the anti-aging industry supposedly promotes to make us live longer in several ways.

It turns out that the super-old sisters probably lived that long due to high levels of pro-oxidants and low levels of antioxidants, as well as constant low-level inflammation. Philippa had an unhealthy cholesterol profile and the sisters apparently shared a sweet tooth.

Aging in biological terms means changing over time. Therefore, the only anti-aging strategy is to stop being alive or take a ride in a time machine. However, as is clear in this time of pandemic, popular ideas don’t always make scientific sense.

Consider Sephora, the chain of cosmetics packed with skincare superstores and products. Their anti-aging elixirs include peels, serums, polypeptide moisturizers, oils, the absolutely useless collagen (a molecule too large to fit under the skin) piteraessence (a miracle ingredient in sake; as soon as I Googled it Facebook searched sell it to me), lactic acid, retinol cream, leech nuts, hyaluronic acid and, of course, the inevitable antioxidants.

Questions and measures

The sisters have lived their entire lives in Canicatt, Sicily. What made them run so long?

They answered wide-ranging questions.What had made each sister sick? What drugs had they taken? Did they smoke?The tests assessed depression, cognition, activities of daily living, ability to perform complex tasks, and eating and sleeping habits. I didn’t see a mention of exercise.

Metrics included body mass index and bioelectrical impedance analysis. The BIA measures fat versus lean muscle mass via a weak electrical current passed through the back of a hand and foot.

Family history was straightforward, revealing longevity and colon cancer.

Filippa and Diegas’ father Calogero Cammalleri died at 97 of unknown causes, and their mother Maria Di Pasquale died at 73 of cancer. Twins died of colon cancer and a third son in an accident.

Diega taught in an elementary school; Filippa reached the fifth grade. The sisters never married and lived together in an apartment. They were wealthy enough to afford a live-in carer.

The sisters never smoked, slept 5 to 6 hours a night and took antihypertensive, diuretic and antiplatelet drugs. Diega had macular degeneration and Filippa had cataracts. Both suffered from osteoarthritis (a breakdown of joint cartilage without inflammation) and osteoporosis.

Filippa was hospitalized at the age of 100 for a broken femur and five years later for constipation. She had mild dementia. So their medical histories were meaningless.

anti aging cream x

Only in the last decade had the sisters needed help getting dressed, grooming, going to the bathroom, getting around, and eating. During those last 10 years, they also weren’t able to prepare meals, take care of their finances, do housekeeping, use the phone, and manage medications.

As for eating habits, the Cammalleri sisters did not follow the much-vaunted Mediterranean diet. They liked pasta, extra virgin olive oil, milk and fruit, but ate vegetables only two or three times a week. The nuns ate pastries and/or biscuits twice a day, eggs and potatoes once. They ate red or smoked meat once or twice a month, but preferred white-meat chicken and oily fish. The investigators found their diet, mainly based on legumes, to be monotonous.

Dig deeper into the data

The sisters were small and thin, technically enough for the word cachexia to appear: wasting syndrome. Each woman was just over 5 feet tall, Filippa weighing 110 pounds and Diega 117. One of the physiological tests (for PhA, also known as polyhydroxyalkanoate) attributes their tiny bodies to fluids leaking from their cells.

I analyzed the four tables of test results to see if my interpretation matched the researchers’ conclusions. And it did.

The list of tables:

  • Anthropometric and body composition values
  • Blood analysis
  • Oxidative and inflammatory tests
  • Limited genetic testing (few genes and microRNAs)

Tables are a nice visual way to present results. Each has four columns. On the far left is the test, then a column for each sister, then a column for the normal range for the metric in healthy Italian women aged 50-65. mathematics.

Only a few bold measurements appeared for all items except oxidative and inflammatory tests. Of those dozens of scorers, the twins were literally off the charts.

vj day x
My grandfather Sam lived to be 103 years old. He ate his favorite meal, fried crab, every day.

Paradoxical antioxidant patterns and microRNAs drive inflammation

The sisters had low levels of antioxidants, such as PON (paraoxonase) and GSH (glutathione), and the sulfur-containing amino acids needed to produce them. Yet they had high levels of MDA (malondialdehyde), a marker of oxidative stress. The elevated KYN (kynurenine) reflected inflammation throughout the body, which is part of the innate immune response.

The results for microRNAs were also revealing. MicroRNAs are tiny RNA molecules that turn different combinations of genes on and off, preventing some of them from being transcribed and translated into proteins. They are described as the weakest switches for the genome. The combinations of the approximately 2,500 microRNAs in the human genome oversee and fine-tune protein production.

Levels of three types of microRNAs circulating in the sisters’ bloodstreams conferred what the researchers call a longevity phenotype, a level of inflammation that is normal for a much younger person.

Has an immune system been allowed to simmer on the low heat responsible for a long life without infectious disease?

Limited genetic information

The genetic analysis was of only a few markers of aging, not a genome-wide landscape of single-base markers (SNPs) or an exome or genomic sequence.

The researchers looked at two genes associated with aging:FOXO3AANDApoE.

At one point in the Forkhead O3A (FOXO3A) box, a person may have two DNA bases of GG, two of TT, or one of each, TG. Having a G has been linked to longevity. Filippa was TG and Diega TT. It turns out that the association is valid only for some populations, Sicilians not among them.

Also on the menu were ApoEgene variants 2, 3, and 4. This gene is widely known for its association with Alzheimer’s disease risk: variant 4 increases risk, 2 lowers it, and the more common variant 3 is neutral. The sisters had boring 3 variants. Again, genetic associations do not apply to Sicilians.

Going back to metabolism for a moment because it’s under genetic control, the sisters had borderline unhealthy cholesterol profiles. Diega had low HDL and Filippa had low HDL and also high LDL.

telomere caps xTelomeres were measured. These are the chromosomal spikes that normally reduce with age. One might expect longer telomeres in people who live long lives, but the sisters were again normal.

There is precedent for the discovery that low-level inflammation keeps some people alive for a long time. A 2015 paper, Inflammation, But Not Telomere Length, Predicts Successful Aging at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians, by researchers at the Center for Supercentenarian Research, Keio University School of Medicine, Tokyo, found that this is a common finding among most of the 1,554 very old people they analysed.

We conclude that inflammation is an important malleable driver of aging to extreme old age in humans, they wrote.

What does it mean?

The two sisters who passed 100thbirthdays in relatively good health had:

  • Elevated LDL cholesterol
  • Moderate and persistent inflammation
  • Oxidative stress
  • Consumption of sweets twice a day
  • Limited vegetables
  • No ApoE genes protective against Alzheimer’s

Diega and Filippa are clearly outstanding. But they argue that one-size-fits-all medicine isn’t always the best way to evaluate health. Newspaper articles applaud precision medicine, but the average healthcare consumer is unlikely to encounter it.

My primary care provider has never asked me a single thing about my family health history. Had he discovered that there is no cardiovascular disease at all, but unhealthy cholesterol profiles. He wants me to take a statin. Well no. He keeps prescribing naproxen, even though it makes me sick, because insurance companies and protocols recommend giving it first because ibuprofen irritates the digestive lining. But ibuprofen only does it in one percent of the population, and that’s not me.

Diega and Filippa were lucky, we don’t know if they actively did anything to prolong their lives. But the subtext of studying biologically exceptional people is that we learn more about how we vary. And healthcare professionals should consider that their patients may be exceptions to medical rules.

Ricki Lewis has a PhD in genetics and is the author of the textbook Human Genetics: Concepts and Applications, forthcoming in its 14th edition. Follow her on her website or on Twitter@rickilewis

A version of this article was originally posted on Plos Blogs and has been reposted here with permission. PLOS can be found on Twitter @PLOS

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