Some people reach 100 without developing the diseases that kill most of us. Whether they pass that resistance to their children has been an open question for two decades, mostly because the studies designed to answer it looked at a single population at a single point in time.

A study published in JAMA Network Open followed three populations for up to 29 years. Researchers at Albert Einstein College of Medicine, Boston University, and Tufts Medical Center compared 2319 centenarians’ offspring, defined as adults with at least one parent who lived to age 100 or older, with a control group of 2703 people whose parents had shorter lifespans.

The cohorts were drawn from an Ashkenazi Jewish population in the Bronx, New York, that Albert Einstein College of Medicine has followed since 2008 through its LonGenity study, the New England Centenarian Study, which has enrolled since 1995, and the UK Biobank, where outcomes come from linked national health records rather than self-report.

At any given age, centenarians’ offspring were 42% less likely to die. They were 33% less likely to develop cardiovascular disease and 32% less likely to develop hypertension, and when those conditions did arrive, they came later, about 3 years for death and 5 years for hypertension.

When the researchers adjusted for smoking, diet, exercise, alcohol use, education, and socioeconomic status, the hazard ratios barely moved.

None of that is very surprising.

However, one finding prompted the study’s senior author, Sofiya Milman, MD, professor of medicine and genetics and director of Human Longevity Studies at the Albert Einstein School of Medicine in the Bronx, to say this: “I’ll be very frank; we didn’t expect that.” 

She was talking about cancer, the one outcome where centenarians’ offspring looked no different from the control group.

Why Offspring, Not Centenarians

Centenarians themselves are hard to study. “When you study centenarians, you don’t know how they actually got there,” Milman said. “You often cannot say, is it protective or is it just a marker of very, very old age.” By the time someone reaches 100, most of their birth cohort is dead, so there is no matched comparison group, and any biological measurement taken at that age might reflect what got the person there or what is about to kill them.

Studying the offspring of centenarians resolves both problems. They share half their genome with a centenarian parent, they are young enough to have living peers, and they can be followed forward in time to see when disease arrives, if it does. The New England Centenarian Study reported in 2004 that centenarians’ offspring had 62% lower all-cause mortality and 85% lower coronary heart disease mortality than the control group. Albert Einstein College of Medicine’s LonGenity cohort found in 2017 that offspring of parents who lived past age 95 had lower cardiovascular disease prevalence, with no difference in smoking, alcohol use, physical activity, or diet.

But those analyses, and most others in the field, were either cross-sectional or confined to a single population.

The three-cohort structure is what Joris Deelen, PhD, found most useful. Deelen, an associate professor at Leiden University Medical Center in Leiden, Netherlands, studies the genetics of human longevity and has led some of the largest genome-wide analyses of longevity-associated variants, including a meta-analysis cited in the Reed study.

“What they did additionally is that they included three different populations, which was not done before,” Deelen said.

The reported hazard ratios may also understate the protection. A centenarian’s child has a 50% chance of inheriting any given variant from that parent, which means the offspring group is a mix of carriers and noncarriers.

“You would expect that about half of them did not inherit those variants, and half of them did,” Deelen said. “So, your signal gets diluted.”

The 42% reduction in mortality risk is an average across a group in which an unknown proportion of members may carry no more genetic protection than the control group does. Among those who did inherit the variants, the protection may be stronger, and the question is what, biologically, that protection consists of.

The Cancer Exception

Centenarians’ offspring being no more protected than the control group when it came to cancer was not what Milman expected. One explanation, she said, is over-screening. For example, a healthy 75-year-old gets screened for everything, and screening finds indolent cancers, particularly prostate and thyroid subtypes, that would never have caused symptoms.

“They would have died with that cancer, as opposed to from that cancer,” Milman said. 

Another explanation is that centenarians’ offspring get cancer at the same rate but survive it better. The 2004 New England Centenarian Study analysis found 71% lower cancer-specific mortality in centenarians’ offspring. The current study measured incidence, not mortality.

Jalees Rehman, MD, head of biochemistry and molecular genetics at the University of Illinois College of Medicine in Chicago, read the cancer result differently. Rehman, trained as a cardiologist, now studies vascular biology and immunology in aging. “When I read this paper and especially the strong findings on the cardiovascular stroke side, it to me kind of screamed strong endothelial health that’s maybe passed on across generations,” Rehman said.

Endothelial cells line every blood vessel in the body. Healthy endothelium produces nitric oxide, which lets vessels dilate. It resists atherosclerotic plaque formation. And it controls which immune cells cross into surrounding tissue. Loss of any of those functions drives cardiovascular disease, hypertension, and stroke.

Cancer “is not directly affected by healthy, unhealthy vasculature,” Rehman said. A single inherited trait, robust endothelium, would explain protection against three outcomes and not the fourth.

A Lack of Molecular Data

The latest study did not measure hormones, genotypes, or methylation, and the mechanistic hypotheses behind resilience in aging seen in centenarians’ offspring come from separate work. The Albert Einstein College of Medicine group has spent many years building a case that reduced signaling through the growth hormone and insulin-like growth factor 1 pathway (IGF-1) is central to exceptional longevity. 

In 2008, Albert Einstein College of Medicine researchers reported IGF-1 receptor mutations enriched in centenarians. In 2014, Milman and her colleagues found that lower circulating IGF-1 predicted survival among people with exceptional longevity. Last year, they also published on rare coding variants in the IGF-1 gene itself. Milman described a switch that happens around age 50. Though growth hormone and IGF-1 are necessary for development, “as people get older, growth is no longer a good thing,” she said.

Growing cancers may be driven by growth factors, once beneficial, now detrimental. “There occurs a switch, and we think it happens probably around age 50 or so, where having less growth hormone actually becomes beneficial to individuals,” she explained. 

Deelen was not persuaded that the IGF-1 evidence is as strong as the Albert Einstein College of Medicine group presents it. “I think the evidence is a bit less strong because they didn’t functionally test it,” he said.

The receptor variants were identified statistically and characterized in cell lines, not introduced into animals to see what they do in a living system. His own lab uses clustered regularly interspaced short palindromic repeats to insert longevity-associated variants into cell lines and, more recently, mice. He’s found variants in different genes across different families converge on the same downstream effects. At the genetic level, he said, “there’s actually a very strong inverse genetic correlation between cardiometabolic traits and longevity,” while “for cancer that genetic correlation is not that strong.” 

“It’s hard for me to believe that any one biological pathway or factor is so central to driving the resilience to aging,” Rehman said. His lab’s work points to inflammation, which does not run through a single gene or cytokine. It runs through networks of cytokines and transcription factors that reinforce one another, so blocking one does not shut down the rest.

The endothelium sits at the center of that network as “the gatekeeper of immune cells entering tissues,” Rehman said. “If you have a healthy endothelium, you’re less likely to allow immune cells to enter when they’re not needed, and you’re more likely to heal after an injury, so that the inflammation subsides.”

Standard biobank measures, cholesterol and blood pressure, are indirect, he said, but a direct measure he proposes is functional: how much a blood vessel dilates when tissue demands oxygen. “My hypothesis would be that the centenarian offspring would have better endothelial functional measures,” Rehman said.

The Path to a Drug

Milman’s group is working toward harnessing the unique biology present in these populations and building a drug to possibly replicate at least a part of it in others. The group is developing a growth hormone receptor antagonist designed for chronic use in older adults. Preclinical testing in rodent Alzheimer’s models is underway with Milman’s group at Albert Einstein College of Medicine, but no results have been published.

“The rest of us who don’t have exceptional longevity in our families can take the drug that will recapitulate the function of that protective gene or protective protein, and that is really the end game for us,” Milman said.

Deelen’s view is that a single agent is unlikely to reproduce what the variants do. Rapamycin, which inhibits the mTOR pathway downstream of IGF-1, is already available. But rapamycin “hits it with a hammer,” he said, while the natural longevity variants produce milder effects that “do additional things on top.” Targeting the IGF-1 receptor directly, he said, may be “too upstream” and carry the same tolerability problem. “I think you probably need combinations of drugs, and that’s going to be quite challenging.”

Rehman agreed on the combination point but arrived from a different direction. Exercise, he said, is the best existing intervention precisely because “it activates whole networks of resilience, networks of anti-senescence, networks of vascular health.”

Senescent cells have stopped dividing but do not die. They accumulate in tissues with age and release inflammatory signals that damage neighboring cells. Senolytics, drugs that clear them, remove the cells, but “what you’re not doing is removing the cause that made that cell senesce in the first place,” Rehman said.

Future drug development, he said, would need to target vascular aging, senescence, and inflammation at the same time.

What the Findings Don’t Mean

Milman was direct about the limits of the study. “Healthy lifestyle is very, very important and absolutely will benefit 99.9% of us who don’t have longevity in our families,” she said. “However, to say that that’s how centenarians got there, I think, is a misconception.”

After 16 years of following the LonGenity cohort, she said the thing that stands out about centenarians’ offspring is that “they’re busy, they’re still working, they volunteer. They can’t even come in for visits.”

Rehman expects the genetics, once sequenced, to show something specific. A single nucleotide polymorphism (SNP) is a one-letter variation in DNA. What he predicts in centenarian families are SNPs that turn inflammatory signaling down enough to let inflammation resolve after an injury or infection, but not so far down that the immune system fails to clear pathogens.

“You have to have the Goldilocks just right with SNP,” he said. “I think that’s what we’re going to find if we sequence the genomes of the SuperAgers, of the centenarians, and their offspring.”

Deelen and Rehman reported having no relevant financial relationships. Milman reported receiving grants from the American Federation for Aging Research and the National Institutes of Health, as well as personal fees from the XPRIZE Foundation, and reported holding a pending patent for pegylated growth hormone receptor antagonists in the treatment of Alzheimer’s disease and aging. Disclosure information for study authors is available in the original study publication.