How Does Caloric Restriction Enable Longevity? Part II: Surprisingly, Not From Weight Loss

Healthy Aging

More Evidence That Overall Resilience Extends Longevity

It’s International Longevity Month, which coincides well with a big study published in Nature that evaluated how dietary restriction extends longevity. Last week, we covered this study’s findings that extreme dietary restriction increased red blood cell resilience (aka made stronger red blood cells) to positively influence longevity. This week, let’s talk about what this study revealed about weight loss and longevity. Or perhaps more appropriately, what it didn’t find…

What were the key findings from this study again?

Di Francesco et al. evaluated the effects of lifelong dietary restriction and intermittent fasting among 1,000 genetically varied mice. While studying which effects, such as body weight and blood values, of these dietary practices had the most influence on longevity, they found the following:

• Serious dietary restriction = longer life. Of the different dietary interventions, consistently restricting daily dietary calories by 40% throughout life resulted in the longest lives.
• Resilience = longer life. Maintaining healthy body weight, red blood cells, and immune responses with age had the greatest influence on longevity.
• Weight loss and lower glucose ≠ longer life. While body weight loss and improved glucose handling did occur among many dietary restricted mice, these effects did not influence longevity.
• Genes win, at least over dietary restriction. Genetics had a significant influence on which dietary restricted mice had the longest lifespan.

So, let’s dive into the surprising findings around body weight and longevity.

When it comes to longevity, a body weight paradox was discovered.

Di Francesco et al. showed an interesting paradox when it came to body weight, dietary restriction, and longevity. Specifically, they found the following:

• Consistent with many studies, young mice with the highest body weight had shorter lifespans.
• Both dietary restriction and intermittent fasting resulted in lower body weight.
• As shared above, dietary restriction resulted in extended longevity.

On the surface, these points appear to support that losing body weight via dietary restriction helps mice live longer. But thanks to their use of 1,000 genetically diverse mice, this team was able to uncover two really important findings:

• The association between higher body weight and shorter longevity became weaker as mice became adults.
• Further, during their oldest years, the tables turned. Older mice with higher body weights had longer lifespans.

Wait, what? How can dietary restriction, which extended longevity, also cause body weight loss throughout life, which shortened longevity? Hence, the paradox.

So, how to solve this conundrum?

Good question. Here are a couple of key points:

• First, it is important to note that not all dietary restricted mice lived longer. In fact, Di Francesco et al. showed there was remarkable individual diversity in life spans in this group.
• Second, when they looked into differences between dietary restricted mice that lived the longest versus those that did not, they showed that one of the top influences of extended longevity in mice wasn’t body weight loss, but instead it was maintained body weight throughout their lives.

Which gets us back to last week’s theme of resilience. Mice that had their daily caloric intake decreased by 40% throughout their lives effectively underwent a lifelong state of being physiologically stressed. And the mice that were able to maintain their body weights throughout this stressor – the ones that were most physically resilient – lived the longest.

Thus, body weight loss throughout life, especially during the oldest years, is not an indicator of a longer life. In contrast, keeping a healthy body weight (and even having some extra padding) with advanced age does support longevity.

This body weight paradox holds true for us humans, too.

As covered by Lorenzini, there is a U-shaped curve linking body mass index (BMI) with all-cause mortality in humans. Too-high BMI, our lives are shortened. Too-low BMI, our lives are shortened. Somewhere in the middle is the sweet spot for our longevity… and that specific sweet spot changes, based on our age. Especially during our oldest years, where having a higher BMI can be advantageous to our longevity.

How about that? Resilience wins again.

Combining results from the Di Francesco study that we covered this week and last week, there is a common theme. Namely, that resilience is the key to our longevity. This includes the ability to:

• Maintain strong red blood cells.
• Maintain healthy immune responses (including taming pro-inflammatory cytokines and supporting antibody-producing B cells).
• Maintain healthy body weight, including a healthy reserve as we reach our oldest years.

In their review, Ukraintseva et al. emphasize that protecting our biological resilience for as long as possible effectively protects us against the age-related conditions that lead to our demise. The latest study supports this goal.

Next week, we’ll cover why there was so much variation in biological resilience and longevity, even among the dietary restricted mice (hello, genes). In the meantime, have a great week, everyone! And, stay resilient.