Parabiosis and young blood: revision 2 to 3

Revision 2

Revision 3

categories: ["longevity"]

tags: ["parabiosis", "plasma", "aging", "gdf11", "rejuvenation", "clinical trials"]

summary: "Experiments joining the circulation of young and old animals, and the attempts to translate their rejuvenating effects into plasma-based treatments for humans."

summary: "Experiments joining the circulation of young and old animals, and the attempts to translate their rejuvenating effects into plasma-based treatments for humans."

updated: "2026-10-28"

updated: "2026-10-29"

humanEvidence: "Human work is limited to small plasma-infusion and plasma-exchange studies reporting feasibility, biomarker shifts, and one debated subgroup result; every rejuvenation and lifespan finding is from mice."

humanEvidence: "Human work is limited to small plasma-infusion and plasma-exchange studies reporting feasibility, biomarker shifts, and one debated subgroup result; every rejuvenation and lifespan finding is from mice."

access: "Not approved for aging anywhere; plasma products are licensed only for medical indications, and clinics in loosely regulated jurisdictions sell young-donor infusions of the kind the FDA warned against in 2019."

access: "Not approved for aging anywhere; plasma products are licensed only for medical indications, and clinics in loosely regulated jurisdictions sell young-donor infusions of the kind the FDA warned against in 2019."

reversibility: "reversible"

**Parabiosis and young blood** refers to a line of experiments in which the circulatory systems of a

young and an old animal are joined, and to the effort to extract from those experiments a treatment

that can be given to people. Heterochronic parabiosis in mice improves tissue repair, neurogenesis,

that can be given to people. In mice, heterochronic parabiosis improves tissue repair, neurogenesis

and several molecular measures of age in the older partner, which is among the more striking results

and several molecular measures of age in the older partner, one of the more striking results in

in biogerontology. The translation has been troubled: the best-known candidate factor is disputed, an

biogerontology. Translation has been troubled. The best-known candidate factor is disputed, an

alternative interpretation attributes the effect to dilution rather than to anything youthful, and the

alternative interpretation attributes the effect to dilution instead of anything youthful, and the

human market ran far ahead of the science.

## The experiments

Surgical parabiosis, in which two animals are joined along a flank incision so that a shared

In surgical parabiosis, two animals are joined along a flank incision so that a shared vasculature

vasculature develops, dates to Paul Bert's rat experiments in 1864 and was used through the

develops. The technique dates to Paul Bert's rat experiments in 1864 and was used through the

twentieth century to study endocrine and metabolic signals. Mid-century work reported that old rats

joined to young partners survived longer than unjoined controls, in studies with small numbers and

considerable surgical mortality.

The modern field begins in 2005, when Conboy and colleagues showed that exposing an old mouse to a

young circulation restored the activation of muscle satellite cells and liver progenitors, largely by

young circulation restored the activation of muscle satellite cells and liver progenitors, largely

recovering Notch signalling.[^conboy2005] The aged cells themselves were not irreversibly damaged;

by recovering Notch signalling.[^conboy2005] The aged cells themselves were not irreversibly

they were responding to their environment. That reframing connected the result directly to

damaged; they were responding to their environment. That reframing tied the result directly to

[[stem-cell-exhaustion]], and suggested that a share of what looks like intrinsic aging is imposed by

[[stem-cell-exhaustion]]. It also suggested that circulating signals impose a share of what looks

circulating signals — a systemic account of the [[hallmarks-of-aging]] rather than a cell-autonomous

like intrinsic aging, a systemic account of the [[hallmarks-of-aging]] in place of a cell-autonomous

one. The candidate signals include the secreted products of [[cellular-senescence|senescent cells]]

and the chronic immune activation of [[inflammaging]], which is why senescent-cell burden and plasma

composition are often studied together.

Subsequent work extended the finding to the brain. Old blood was shown to impair neurogenesis in

Later work extended the finding to the brain. Old blood was shown to impair neurogenesis in young

young mice, implicating specific circulating chemokines, and young plasma alone was reported to

mice, implicating specific circulating chemokines, and young plasma alone was reported to improve

improve synaptic plasticity and performance on memory tasks in old mice.[^villeda2011] Umbilical cord

synaptic plasticity and performance on memory tasks in old mice.[^villeda2011] Umbilical cord plasma

plasma produced similar effects, with the metalloproteinase inhibitor TIMP2 identified as one

produced similar effects, with the metalloproteinase inhibitor TIMP2 identified as one

mediator.[^castellano2017] A 2023 study reported that a period of heterochronic parabiosis followed

by separation left old mice with reduced epigenetic-age estimates and a modest increase in remaining

by separation left old mice with lower epigenetic-age estimates and a modest increase in remaining

lifespan.[^zhang2023]

## The GDF11 dispute

The clearest example of the field's difficulties is GDF11, a circulating TGF-β family protein.

GDF11, a circulating TGF-β family protein, shows the field's difficulties most clearly. Beginning in

Beginning in 2013, one group reported that GDF11 declines with age and that restoring it reverses

2013, one group reported that GDF11 declines with age and that restoring it reverses cardiac

cardiac hypertrophy, improves skeletal muscle regeneration, and enhances brain

hypertrophy, improves skeletal muscle regeneration and enhances brain vasculature.[^loffredo2013]

vasculature.[^loffredo2013] The papers appeared in leading journals and drove substantial commercial

The papers appeared in leading journals and drove substantial commercial interest.

interest.

A rebuttal from an industrial group in 2015 reported the opposite: that the antibodies and assays

In 2015 a rebuttal from an industrial group reported the opposite. It found that the antibodies and

used could not distinguish GDF11 from the closely related protein myostatin, that GDF11 does not

assays used could not distinguish GDF11 from the closely related protein myostatin, that GDF11 does

decline with age in the way claimed, and that administering it impairs rather than improves muscle

not decline with age in the way claimed, and that giving it impairs muscle regeneration instead of

regeneration.[^egerman2015] The exchange has never been fully resolved. It bears directly on

improving it.[^egerman2015] The exchange has never been fully resolved. It bears directly on

[[myostatin-inhibition]], since the two proteins share receptor pathways and much of the reagent

problem.

> [!debate] Young factors or old factors?

> The intuitive reading of parabiosis is that young blood supplies something restorative. The

> alternative is that old blood contains inhibitory factors and the young partner simply dilutes

> them. Replacing about half the plasma of old mice with saline and albumin (no young blood at all)

> them. Replacing about half the plasma of old mice with saline and albumin, with no young blood at

> produced improvements comparable to parabiosis in several tissues.[^mehdipour2020] If dilution is

> all, produced improvements comparable to parabiosis in several tissues.[^mehdipour2020] If

> the mechanism, the therapeutic target is removal, not transfusion.

> dilution is the mechanism, the therapeutic target is removal, not transfusion.

## Confounds

Parabiosis is a crude instrument. Joined animals share far more than plasma: the young partner's

kidneys, liver, lungs, spleen, and bone marrow filter and service both bodies. An old animal in

kidneys, liver, lungs, spleen and bone marrow filter and service both bodies. An old animal in

parabiosis effectively acquires a second set of young organs, and improvements in its tissues may

parabiosis in effect gains a second set of young organs, and improvements in its tissues may reflect

reflect better clearance of metabolic waste rather than the delivery of any signalling molecule.

better clearance of metabolic waste and not the delivery of any signalling molecule. Immune cells

Immune cells cross between partners. Feeding, activity, and thermoregulation change. Results from

cross between partners, and feeding, activity and thermoregulation change. Results from plasma

plasma transfer alone, which removes most of these confounds, are consistently weaker than results

transfer alone, which removes most of these confounds, are consistently weaker than results from

from surgical joining — a pattern that argues the organ-sharing component is substantial.

surgical joining, a pattern suggesting that organ sharing contributes substantially.

The relevant circulating factors are also not necessarily "youth" factors in any general sense.

Nor are the relevant circulating factors necessarily "youth" factors in any general sense. Plasma

Plasma from exercised mice transfers benefits to sedentary ones, and exercise changes the same broad

from exercised mice transfers benefits to sedentary ones, and exercise changes the same broad

classes of protein. The distinction between a rejuvenation signal and an ordinary

classes of protein. No one has cleanly separated a rejuvenation signal from an ordinary

[[exercise-and-aging|exercise response]] has not been cleanly drawn.

[[exercise-and-aging|exercise response]].

## Human attempts

Human work has taken three forms, none of which has produced convincing evidence of benefit.

Human work has taken three forms, and none has produced convincing evidence of benefit.

*Plasma infusion trials.* A small study infusing plasma from young donors into patients with

Alzheimer's disease established feasibility and tolerability without addressing efficacy, and the

Alzheimer's disease established feasibility and tolerability without addressing efficacy. The

company behind it moved toward defined plasma fractions rather than whole plasma before being

company behind it moved toward defined plasma fractions instead of whole plasma before it was

acquired. A separate line of work using therapeutic plasma exchange with albumin replacement in

Alzheimer's reported slowed decline in a subgroup, a result that remains debated.

*Commercial young-plasma clinics.* A US startup sold transfusions of young donor plasma to paying

customers for general anti-aging purposes. In 2019 the FDA issued a public statement warning that

infusions of plasma from young donors for aging, memory, or other conditions have no proven benefit

infusions of plasma from young donors for aging, memory or other conditions have no proven benefit

and carry the known risks of transfusion, including allergic reaction, circulatory overload, and

and carry the known risks of transfusion, including allergic reaction, circulatory overload and

infection.[^fda2019] The clinic model has recurred in less regulated jurisdictions since.

infection.[^fda2019] The clinic model has recurred since in less regulated jurisdictions.

*Plasma exchange in healthy adults.* Small studies of therapeutic plasma exchange in older

volunteers have reported changes in inflammatory and proteomic panels and in

[[epigenetic-clock|clock-based]] age estimates. A sham-controlled trial published in 2025

[[epigenetic-clock|clock-based]] age estimates. A sham-controlled trial published in 2025 assigned

assigned 42 adults over 50 to plasma exchange with albumin replacement (in one arm with added

42 adults over 50 either to plasma exchange with albumin replacement (in one arm with added

intravenous immunoglobulin) or to a sham procedure. Several epigenetic clocks read lower than in the

sham group at an intermediate sampling point, no group differed significantly from sham at the final

sham group at an intermediate sampling point, but no group differed significantly from sham at the

one, and functional, cognitive and symptomatic outcomes were not assessed.[^fuentealba2025] These are

final one, and functional, cognitive and symptomatic outcomes were not assessed.[^fuentealba2025]

surrogate measures, and a shift in a [[biological-age|biological-age estimate]] is not evidence of

These are surrogate measures, and a shift in a [[biological-age|biological-age estimate]] is not

functional improvement. The most publicized individual case, that of [[bryan-johnson]] in 2023, was

evidence of functional improvement. The most publicized individual case, that of [[bryan-johnson]]

not a two-way swap: plasma from his 17-year-old son was infused into Johnson, and Johnson's plasma

in 2023, was not a two-way swap. Plasma from his 17-year-old son was infused into Johnson, and

into his 70-year-old father, as one of six monthly one-litre "young plasma exchanges" in his heavily

Johnson's plasma into his 70-year-old father, as one of six monthly one-litre "young plasma

measured [[quantified-self]] regimen. In July 2023 Johnson announced that he was discontinuing them

exchanges" in his heavily measured [[quantified-self]] regimen. In July 2023 Johnson announced that

because his biomarkers showed no benefit, a single uncontrolled self-report.[^fortune2023]

he was stopping them because his biomarkers showed no benefit, a single uncontrolled

self-report.[^fortune2023]

## Risks

Plasma is a biological product with an established risk profile: transfusion reactions, transfusion-

Plasma is a biological product with an established risk profile: transfusion reactions,

associated circulatory overload, transfusion-related acute lung injury, and residual infectious risk.

transfusion-associated circulatory overload, transfusion-related acute lung injury and residual

These risks are accepted in the treatment of bleeding or immune disease and are not obviously

infectious risk. These risks are accepted in the treatment of bleeding or immune disease, but they

acceptable in a healthy person pursuing an unproven benefit. Repeated large-volume exchange also

are not obviously acceptable for a healthy person pursuing an unproven benefit. Repeated

removes clotting factors, antibodies, and drugs along with whatever the target is, and requires

large-volume exchange also removes clotting factors, antibodies and drugs along with whatever the

replacement fluids that carry their own costs. The donor-supply implications of a large market for

target is, and it requires replacement fluids that carry their own costs. A large market for young

young plasma, and its interaction with existing blood-donation systems, are a distributional problem

plasma would raise donor-supply questions and interact with existing blood-donation systems. That is

in their own right, related to those discussed under [[access-and-inequality]] and to the wider

a distributional problem in its own right, related to those discussed under

search for [[artificial-blood|manufactured blood products]].

[[access-and-inequality]] and to the wider search for

[[artificial-blood|manufactured blood products]].

## Outlook

The productive residue of this line of work is not transfusion. It is the identification of specific

What this line of work has produced of lasting use is not transfusion. It has identified specific

circulating proteins that change with age and have measurable effects when manipulated — a target

circulating proteins that change with age and have measurable effects when manipulated, a target

list that feeds into [[gene-therapy-for-aging|systemic gene therapy]], recombinant protein programmes,

list that feeds into [[gene-therapy-for-aging|systemic gene therapy]], recombinant protein

and the broader project of [[aging-biomarkers|measuring systemic aging]]. Klotho, TIMP2, and

programmes and the broader project of [[aging-biomarkers|measuring systemic aging]]. Klotho, TIMP2

exercise-induced factors are being pursued individually, where dose and mechanism can be controlled

and exercise-induced factors are being pursued individually, where dose and mechanism can be

in a way that whole plasma never allows.

controlled in a way whole plasma never allows.

Removal is the mirror strategy. If old plasma carries inhibitory factors, the therapeutic act is

subtraction — targeted apheresis for specific proteins, or clearance of the cells producing them,

subtraction: targeted apheresis for specific proteins, or clearance of the cells producing them,

which is the logic of [[senolytics]]. Either version would have to be tested against

[[healthspan|functional endpoints]] rather than the biomarker panels that dominate current reports.

[[healthspan|functional endpoints]] and not against the biomarker panels that dominate current

reports.

The open question is whether the parabiosis effect will decompose into a small number of tractable

The open question is whether the parabiosis effect will break down into a small number of tractable

molecules or whether it depends on the wholesale exchange of a circulatory environment. If the latter,

molecules or depends on wholesale exchange of a circulatory environment. If the latter, there may be

there may be no drug on the other side of these experiments at all — only the demonstration that aged

no drug on the other side of these experiments at all, only the demonstration that aged tissue

tissue retains more capacity than it displays, which is the same premise driving

retains more capacity than it displays. That is the same premise behind

[[epigenetic-reprogramming]].

## See also