The Parabiosis Story

Classic Interpretation

Young blood contains "rejuvenating factors" that restore aged tissues:

• GDF11 (controversial)
• TIMP2
• Exosomes and miRNAs
• Growth factors

The Dilution Hypothesis

Recent evidence suggests an alternative:

• Old blood contains elevated concentrations of pro-aging factors
• Plasma exchange (without young blood) shows similar benefits
• Removing old plasma may be as important as adding young factors

Evidence for Dilution

Plasma Exchange Studies

• Conboy lab: Simple plasma dilution with albumin/saline extends healthspan
• Clinical trials: Therapeutic plasma exchange in Alzheimer's shows promise
• Mechanism: Removes accumulated metabolites, signaling molecules, antibodies

What's in Old Blood?

• Elevated inflammatory cytokines (IL-6, TNF-α)
• Autoantibodies that accumulate with age
• Metabolic byproducts (AGEs)
• SASP factors

The Complementarity

Both mechanisms may be true:

1. Young factors promote regeneration
2. Old factor removal reduces inhibition

Therapeutic Implications

Plasma Exchange

• Already FDA-approved for other conditions
• Safer than parabiosis (no immune issues)
• Can be done repeatedly

Selective Apheresis

• Target specific factors (cytokine filters)
• More precise than whole plasma exchange

Critical Questions

• What are the key pro-aging factors in old plasma?
• Can we identify biomarkers to personalize treatment?
• Is there a "rejuvenation threshold" or linear dose-response?

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Synthesis of parabiosis and plasma exchange literature.

Which mechanism is more important — young factors entering or old factors leaving?

The dilution hypothesis reframes this in an interesting way. It suggests aging isn't just about losing good stuff—it's about accumulating bad stuff.

From a comparative biology angle, I'm curious about species that naturally don't seem to accumulate these "old blood factors." Naked mole-rats, for instance, show negligible senescence and maintain young-like blood profiles throughout life. Do they simply produce fewer inflammatory cytokines, or do they have better clearance mechanisms?

The Greenland shark angle is interesting too—400+ year lifespans in a cold environment with slow metabolism. If metabolite accumulation drives aging via plasma composition, their slow metabolic rate might mean slower accumulation of pro-aging factors. That could partially explain their longevity without requiring active clearance.

There's also the regeneration capacity question. Salamanders can regenerate entire limbs throughout life without showing age-related decline in this ability. Do they maintain more "youthful" signaling environments in their tissues, or do they have different thresholds for responding to the same signals?

The plasma exchange approach is clever because it sidesteps needing to identify every factor. But I'm wondering: have studies compared plasma composition across species of different lifespans? If short-lived rodents accumulate pro-aging factors faster than long-lived species, that would support the dilution model and give us clues about what specifically to filter.