Cholesterol, Longevity, and a Missing Middle

Re-thinking Lipoproteins Through an Adaptation Lens

A recent review on lipoprotein metabolism and life expectancy proposes an appealing idea: that lipoproteins are not just passive cholesterol carriers, but active participants in aging biology, interacting with major longevity pathways such as AMPK, mTOR, and sirtuins.

At first glance, the framework seems elegant. Different lipoprotein classes are visually linked to nutrient-sensing pathways, and those pathways are in turn connected to interventions like caloric restriction, rapamycin, omega-3 fatty acids, or PCSK9 inhibition.

And yet, for many readers — clinicians included — something feels off.

The arrows don’t quite convince. The logic feels linear, where biology is conditional.

And lipoproteins appear to be doing jobs they were never designed to do.

That discomfort is a clue.

The problem isn’t the molecules — it’s the direction of causality

The review implicitly assumes a flow like this:

Lipoproteins → signaling pathways → longevity interventions

But human physiology rarely works that way.

Lipoproteins do not meaningfully signal to AMPK, mTOR, or sirtuins.

Those pathways respond primarily to cellular energy state, not to whether LDL or VLDL happens to be elevated in plasma.

When we flip the causal order, the biology suddenly makes sense.

An adaptation-first view: ERM and bioenergetic constraint

Through the lens of Exposure-Related Malnutrition (ERM) and stress adaptation, lipoproteins are best understood not as upstream regulators, but as downstream logistics readouts.

Here’s the biologically consistent sequence:

1. Chronic demand accumulates (psychological stress, inflammation, toxic exposures, metabolic load)

2. Bioenergetic capacity becomes constrained (ATP availability, NAD⁺ balance, redox buffering)

3. Mitochondrial throughput is limited. Oxidation and substrate handling can’t keep up with demand

4. Energy-sensing pathways shift

   • AMPK reflects energetic strain

   • mTOR prioritizes growth and storage if unchecked

   • Sirtuins decline as recovery bandwidth shrinks

5. Lipoprotein patterns adapt

   • ↑ ApoB particle output (VLDL → IDL → LDL)

   • ↑ remnant burden

   • ↓ HDL function (efflux, antioxidant capacity)

In this view, lipoproteins are not the cause of dysfunction —they are the visible footprint of an adaptive system under load.

Why LDL can be adaptive — until it isn’t

This reframing explains a long-standing paradox:

• Why LDL can rise during stress, illness, or aging

• Why the same LDL level is benign in some people and harmful in others

• Why lowering LDL sometimes reduces risk but doesn’t restore health

When mitochondrial throughput is limited, the body still needs:

• membranes,

• steroid hormones,

• immune transport,

• tissue repair scaffolding.

Exporting lipid via ApoB-containing particles is a logistical solution.

The problem arises when this state persists without resolution.

What began as adaptation becomes congestion.

Transport turns into retention.

And lipoproteins become oxidized, inflammatory, and pathogenic.

Re-reading the review’s interventions — now with clarity

The interventions proposed in the review actually make more sense when placed correctly in this hierarchy.

• Caloric restriction, fasting, exercise, sleep→ restore bioenergetic throughput→ improve AMPK tone, reduce mTOR pressure, preserve sirtuins

• Omega-3s, Mediterranean patterns, micronutrients→ reduce oxidative and inflammatory load→ preserve HDL function, not just HDL-C

• Statins and PCSK9 inhibitors→ reduce ApoB “traffic volume”→ lower downstream risk without fixing upstream capacity

• Rapamycin→ suppress growth demand→ potentially helpful or harmful depending on energetic reserve

Seen this way, these tools are no longer competing ideologies —they act at different layers of the same adaptive system.

What this reinterpretation adds

The original review is right about one thing: lipoprotein metabolism and longevity are deeply connected.

What it misses is the middle layer — the energetic logic that explains why.

By re-anchoring lipoproteins within an adaptation-first, bioenergetic framework, we gain:

• a coherent explanation for heterogeneity in lipid risk,

• a reason HDL function matters more than HDL levels,

• and a way to integrate cardiometabolic and neurodegenerative aging.

Most importantly, we stop treating cholesterol as the villain —and start asking a better question:

What is the system adapting to, and does it still have the energy to resolve it?

You’re not broken.

You’re adapting — and sometimes, you’re exhausted.

Understanding lipoproteins as signals of energetic constraint, not moral failures of metabolism, opens the door to more humane, precise, and effective longevity care.

Skrzycki, M., & Graboń, W. (2025). Lipoprotein metabolism and its impact on life expectancy. Experimental gerontology, 212, 112952. https://doi.org/10.1016/j.exger.2025.112952