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5 Studies That Should Change Your Longevity Protocol

Author

Piers Moore-Ede
January 19, 2026

Hi there,

Longevity research has a noise problem.

Every week, some headline declares a breakthrough. A molecule “reverses ageing.” A fasting pattern “melts fat.” A supplement “turns on autophagy.” And if you are trying to build a sane, effective protocol, the result is often disregulating.

So in this newsletter I want to do something slower and more useful: walk you through five recent papers that actually change how I think about protocols. Not because they are perfect, or because they solve ageing, but because they sharpen the map.

The theme that runs through all five is this: biology is less like a toolbox and more like a set of interlocking thermostats. Push one lever, and you often discover you were pushing three.

  1. Rapamycin, fasting, and calorie restriction may be arguing about different routes to the same destination

The study (mice): University of Michigan researchers looked across a set of well-known lifespan-extending interventions and asked a simple question: do they share a common molecular signature?

They measured a key player in inflammation called NF-κB p65. NF-κB is a master switch for inflammatory signalling. When it is persistently “on,” it helps keep the immune system in a low-grade, smouldering state that is strongly linked with ageing and chronic disease.

What they found was striking: across multiple interventions (including rapamycin, calorie restriction, and several “longevity-ish” drugs), p65 levels were lower.

That does not mean every intervention is “just inflammation” in disguise. But it does suggest something practical: a lot of what we treat as separate strategies may converge on the same downstream effect, namely turning down chronic inflammatory tone.

The detail I found most useful is the exception. Two male-specific lifespan extenders in mice (17α-estradiol and astaxanthin) did not lower p65. That is a hint that there are parallel pathways worth understanding, and that not everything rolls up neatly into one mechanism.

What this changes in protocol thinking:

If you are stacking multiple interventions that all reduce NF-κB activity, you may not be stacking in the way you think. You may be buying overlap.

So rather than asking “what else can I add,” the smarter question becomes: “What am I trying to move, and is it moving?”

This is where biomarkers stop being a nerd hobby and become common sense. If the aim is reduced inflammatory load, you want to see it in something like hsCRP, and ideally in IL-6 if you have access to it.

If your markers are low and stable already, the returns to additional anti-inflammatory interventions may be smaller than you imagine. If your markers are high and not budging, your protocol may be sophisticated but mis-aimed.

  1. Time-restricted eating works, but mostly because it helps you eat less, not because clocks are magical

Time-restricted eating has been sold as a kind of circadian cheat code. Put your food into an eight-hour window and your metabolism allegedly reorganises itself, even if calories do not change.

A 2025 meta-analysis in The BMJ is a helpful corrective. Looking across intermittent fasting strategies, the authors concluded that intermittent fasting tends to deliver broadly similar benefits to continuous calorie restriction for weight loss and cardiometabolic markers. In plain English: the benefits mostly track the energy deficit, not the window itself.

That might sound deflating, but I think it is actually freeing.

Because it tells you what to focus on.

Time windows are not a substitute for energy balance. They are a behavioural tool that may help energy balance happen without constant counting. Some people find an eating window makes them calmer around food. Others find it makes them weirdly obsessive. The biology is not offended either way. The question is: does it reliably reduce overall intake, improve food quality, and improve sleep?

One nuance worth noting is that not all fasting patterns are equal. Some approaches (like alternate-day fasting) can show slightly stronger effects in some outcomes, especially in shorter trials. But the big picture from this analysis is that intermittent fasting is not a metabolic loophole. It is another way to arrive at the same destination: sustained, tolerable energy reduction for long enough to matter.

What this changes in protocol thinking:

If you are doing 16:8 and your calories and food quality are unchanged, do not assume your metabolic markers will transform. You might still benefit from fewer late-night meals, better digestion, better sleep. But the “metabolic magic” story is overplayed.

If you want the most reliable lever, focus on what you can actually sustain: a modest, consistent energy deficit paired with high food quality.

  1. A “non-essential” amino acid that seems to protect the ageing gut, at least in flies

The asparagine paper is one of those studies that makes you pause because it cuts across a common bit of longevity folk-wisdom.

We often talk about amino acids as ageing accelerants. Too much leucine, too much mTOR, too much growth. Restrict protein, extend life. The story is not wrong, but it is incomplete.

In this study, researchers gave asparagine to ageing fruit flies and found it mitigated age-related dysfunction in intestinal stem cells, supported intestinal homeostasis, and acted through the autophagy-lysosomal pathway. They also report lifespan extension in ageing flies.

Why care about a fly gut?

Because the gut is not just a tube. It is a barrier, an immune organ, a signalling hub. When it degrades with age, it tends to leak inflammatory signals into the system. In many models of ageing, gut integrity is one of the first dominoes to fall.

Asparagine is called “non-essential” because we can synthesise it. But “non-essential” is a nutritional category, not a biological judgement. The more interesting question is whether levels or availability become limiting under certain conditions, especially in ageing tissue.

What this changes in protocol thinking:

It is not a reason to supplement asparagine. There is no human intervention data here that justifies that leap.

It is, however, a reason to be cautious about simplistic protein dogma. Not all amino acids behave the same way in ageing biology, and “protein restriction” is not automatically “longevity.”

Practically, the safe version is food-based: you probably do not need to fear modest amounts of asparagine-rich foods (asparagus, legumes, potatoes, nuts, eggs, fish), especially if your overall diet is strong and your metabolic health is good.

  1. Protein quality may matter as much as protein quantity

If there is one topic that longevity people can argue about endlessly, it is protein. How much. How often. When. Whether we should eat like centenarians or like athletes.

This next study steps sideways from the usual debate and asks a more subtle question: what if the issue is not how much protein you eat, but how well your cells translate proteins?

Every protein begins as a set of instructions on mRNA that gets read by ribosomes. Sometimes ribosomes stall. Sometimes they collide. Sometimes the cell produces truncated, faulty proteins that contribute to proteotoxic stress, one of the hallmarks of ageing.

Ribosome-associated quality control is how cells keep that process clean.

The Pelota study shows that this ribosome rescue factor promotes longevity and protects against age-related phenotypes across multiple species. The implication is not “Pelota is the answer,” since we cannot exactly buy a Pelota supplement. The implication is conceptual: a long life may depend partly on maintaining the fidelity of the translation machinery, not merely turning down total protein synthesis.

That reframes why some people seem to do well with higher protein even later in life, while others benefit from lower protein. The difference might not be just diet. It might be proteostasis capacity.

What this changes in protocol thinking:

Be careful with blanket rules like “less protein equals longer life.” In some bodies, in some contexts, the limiting factor may be protein quality control, not protein load.

Also: the boring stuff starts to look less boring. Micronutrient sufficiency supports the machinery that keeps translation accurate, and that includes basics like zinc, magnesium, and B vitamins. The point is not to panic-supplement. It is to respect that the glamorous interventions often sit on top of unglamorous foundations.

  1. A new autophagy activator that is not rapamycin (but also not for humans)

Autophagy is one of those mechanisms that gets invoked so often it risks becoming a slogan. But the underlying idea is genuinely central: cells need to recycle damaged components to stay functional, and ageing is, in part, a story of failing cleanup.

Rapamycin can activate autophagy partly by inhibiting mTORC1. It is powerful, but it can come with trade-offs and is not a casual compound.

This new paper introduces AA-20, a small molecule that activated autophagy and extended lifespan in C. elegans. The key detail is mechanistic: AA-20 appears to act at least partly via TFEB, a transcription factor involved in lysosomal and autophagy pathways, and it does so without inhibiting mTORC1.

This is not a compound you should be trying to source. It is a research tool at this stage.

What it does offer is a glimpse of where the field is heading: more selective autophagy activators that might deliver some of the benefits without some of the downsides of broad mTOR inhibition.

What this changes in protocol thinking:

It reinforces the idea that autophagy is a central lever, but there may be multiple routes to it.

For now, the “human-grade” autophagy levers remain the familiar ones: exercise, sleep, and periodic energy restriction that you can tolerate. Food-based approaches like spermidine-rich foods are interesting, and I will cover the human evidence properly in a future issue.

The connecting thread

If you take these studies together, a more grown-up picture of protocols emerges:

  • First, many interventions converge downstream, so stacking is not automatically additive.

  • Second, fasting works best when it changes total intake and behaviour, not because the clock itself is enchanted.

  • Third, ageing biology punishes simplistic rules. Amino acids are not one thing. Protein is not one thing. “Autophagy” is not one thing.

  • And finally, measurement beats mythology. If you are serious about longevity, you want feedback loops, not just beliefs.

What I would do this week

  1. Look at your last bloodwork and find hsCRP. If you have never measured it, consider doing so next time. It is one of the cleanest “is my inflammatory load actually low?” signals we have.

  2. If time-restricted eating currently helps you eat better and sleep better, keep it. If it has become a talisman you cling to while calories creep up and dinners get later, simplify the story: focus on overall intake and food quality first.

  3. Make sure your diet is not accidentally austerity cosplay. If you are restricting protein aggressively, ask whether you are doing it for a measured reason, or because you are obeying an internet rule.

  4. Put one autophagy-friendly behaviour back in its rightful place: moving your body regularly, sleeping consistently, and not eating late every night.

One more thing before I go

The asparagine study is a perfect example of why I still read the papers. Reality is usually more nuanced than the slogans, and the body is always more interesting than our arguments about it.

More soon.

Stay sharp,
Piers

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References

  1. NF-κB p65 convergence (mice): https://pubmed.ncbi.nlm.nih.gov/39666139/

  2. Intermittent fasting meta-analysis (BMJ): https://www.bmj.com/content/389/bmj-2024-082007

  3. Asparagine and gut stem cells (Aging Cell): https://onlinelibrary.wiley.com/doi/10.1111/acel.14423

  4. Pelota and ribosome quality control (PNAS): https://pubmed.ncbi.nlm.nih.gov/40758887/

  5. AA-20 autophagy activator (PNAS): https://pubmed.ncbi.nlm.nih.gov/40758884/