Longevity Breakthrough? Why Calorie Restriction Still Leads

April 18, 2025

Longevity: CR ist präklinisch am wirksamsten, mit Vorbehalten

April 18, 2025

Longevity is currently a hot topic. The term seems to be at the peak of the Gartner hype cycle, where enthusiasm is high but, unfortunately, there are still no solid findings.

Promises of anti-aging supplements, miracle molecules, and groundbreaking therapies fill headlines and social media feeds. However, much of what is being marketed today, sometimes very aggressively as scientific, is based on speculation and lacks any clinical, and in some cases even preclinical, evidence.

That's why a talk by Matt Kaeberlein, one of the world's leading longevity experts, recently caught people's attention at the Global Conference on Gerophysics in Singapore.

He offered something that's rare in this noisy environment: a realistic assessment. In his talk, he reminded the audience of something surprisingly simple.

The gold standard for 50 years: calorie restriction

Amidst a flood of marketing-driven optimism, Kaeberlein brought the discussion back to the facts. Backed by decades of research, he delivered an honest and data-driven message: in over 50 years of preclinical research, no intervention has surpassed calorie restriction in extending the lifespan of mammals.

“But I think without a doubt, the gold standard for non-genetic ways to modify lifespan in mammals is caloric restriction.” Matt Kaeberlein

This means that despite all the excitement surrounding drugs and supplements, preclinical studies still achieve the best results with simple calorie reduction.

Calorie restriction, or CR, means consuming significantly fewer calories without being malnourished. A groundbreaking study from the 1980s showed that mice on a calorie-restricted diet lived up to 60 months, significantly longer than mice on a normal diet. This study remains the benchmark for all other measures to this day.

Why Not Even All Mice Are Equal

The study Matt Kaeberlein referred to, originally conducted by Weindruch and Walford in the 1980s, used C57BL/6 mice, also known as Black 6. This strain responds exceptionally well to calorie restriction, which partly explains the impressive results. But if you apply the same intervention to other strains, the outcome can be completely different. About one third of mouse strains live longer with CR, one third show no change in lifespan, and one third actually live shorter lives. Even among mice, longevity is not consistent. This makes it even more challenging to translate preclinical findings into meaningful human outcomes.

Today's longevity interventions in comparison

Kaeberlein compared the results of the now 50-year-old calorie restriction study with preclinical study results such as:

Rapamycin (immunosuppressant and mTOR inhibitor)
Metformin (antidiabetic and AMPK activator)
Senolytics(active substances for eliminating senescent cells)
Intermittent fasting (periodically restricted food intake for metabolic modulation)
NAD+ boosters (NR nicotinamide riboside)
Epigenetic reprogramming (targeted reset of cellular aging markers)

None of these prolonged lifespan in preclinical studies more than calorie restriction. Some even showed only minimal improvements or results were on par with the control group. In other words, some did not improve lifespan at all compared to untreated animals.

“So why can't we do better than caloric restriction? One possibility, and this kind of came up today, maybe CR represents kind of the best we're going to do in mice. Maybe we aren't going to be able to push past that.”
Matt Kaeberlein

This is a very important finding, as many of these interventions are already being sold to consumers or promoted as significant advances, even though relevant results have not even been achieved in preclinical studies. However, in laboratory tests, they were no more effective than the calorie restriction method that has been known for decades. How is this possible?

Preclinical vs. clinical studies

Kaeberlein also emphasized something that is often overlooked. Most of what we know about these interventions comes from preclinical research, i.e., animal and cell experiments.

You can find a text on this topic here:
→ Science-based! For mice or for humans?

Why longevity research needs a reset

Kaeberlein criticized the narrow focus of current research. He argued that science is too oriented toward existing theories and misleading concepts such as the “hallmarks of aging.” While these have guided thinking, they have also limited innovation.

You can find an article on this topic here:
→ The biology of aging: What we know and what we don't

His solution is a return to large-scale discovery research. His project, the Million Molecule Challenge, aims to study more than a million compounds for their effects on the lifespan of worms and make the data openly available.

So what should we believe?

Kaeberlein did not say that people should go on extreme diets. In fact, calorie restriction in humans is still being studied and may not be suitable for everyone. But his argument is simple and powerful.

We should not jump to conclusions.

Until something works better than calorie restriction in well-controlled studies, we should always be very skeptical of big claims. And we should stick to what the data—not marketing—actually shows. At a time when science is being sold as a lifestyle, this talk was a much-needed reminder that real progress is slow and cautious, based on what works, not what sounds good.

Sometimes the biggest breakthroughs are not the newest ones, but those that we still don't fully understand even after 50 years.