“Oxygenaging” as One Layer of Bioenergetic Impedance

A new review in Aging Cell proposes an intriguing way to think about aging. Rather than focusing only on mitochondrial dysfunction, vascular aging, or molecular hallmarks in isolation, Donega and colleagues follow oxygen through the entire physiological journey—from the atmosphere to the mitochondria—and ask what happens when the ability to maintain that flow progressively deteriorates.

They call the framework “Oxygenaging.” Its central idea is that aging is associated not simply with less oxygen, but with a declining ability to continuously match oxygen supply with metabolic demand. Oxygen must move through pulmonary gas exchange, arterial transport, cardiac output, microvascular distribution, tissue diffusion, and finally mitochondrial utilization. Impairment at any of these levels can constrain the effective oxygen available for energetic work.     

Importantly, the authors explicitly state that Oxygenaging should not be interpreted simply as oxygen deficiency. Rather, it reflects progressive loss of resilience in the mechanisms maintaining oxygen homeostasis as physiological conditions change.     

This distinction makes the review particularly interesting from the perspective of our recently published concept of bioenergetic impedance.

A notable convergence in geroscience

One aspect of this review deserves particular attention: Luigi Ferrucci is among its authors.

Ferrucci and colleagues have increasingly emphasized physiological reserve, resilience, perturbation responses, and the distinction between accumulated biological damage and the capacity to respond to stress. Oxygenaging now takes this reasoning into a specific physiological resource system: oxygen.

The conceptual trajectory is striking.

Instead of asking only what molecular abnormalities accumulate with age, the question increasingly becomes:

Can the organism still dynamically match resources to demand, adapt efficiently when challenged, and return toward its previous state afterward?

Oxygenaging approaches that question through oxygen physiology.

Our bioenergetic impedance perspective approaches it from energetic throughput more broadly.

And importantly, our bioenergetic impedance perspective is already published. We are therefore not introducing impedance retrospectively in response to the Oxygenaging paper.

Rather, the two independently developed perspectives can now be compared as conceptually convergent frameworks emerging from different directions.

That is scientifically more interesting than attempting to make one framework subsume the other.

Oxygenaging provides detailed physiology for one major layer of resource delivery. Bioenergetic impedance provides a broader framework for understanding what happens whenever energetic throughput becomes constrained relative to demand.

The overlap points toward a larger systems-level direction that geroscience may increasingly be approaching.

Oxygen availability is not oxygen utility

The physiological details in the review illustrate a deceptively important principle:

Availability does not necessarily translate into delivery, processing, or utility.

Consider oxygen.

A person can breathe normal atmospheric oxygen and maintain apparently acceptable arterial oxygen saturation, yet oxygen may still fail to reach the tissues where it is most needed.

Aging can impair lung mechanics and ventilation–perfusion matching. Maximal cardiac output declines. Microvascular rarefaction increases diffusion distances. Fibrosis alters tissue architecture. Endothelial dysfunction limits vasodilation. Local blood flow becomes slower to respond when metabolic demand suddenly increases.     

Perhaps most revealing is the microcirculation.

The authors explain that total blood flow can remain apparently adequate while local oxygen transfer becomes increasingly heterogeneous. Oxygen may be present in the circulation, but the organism becomes less capable of delivering it rapidly to the specific region where metabolic demand has increased.     Aging Cell - 2026 - Donega - Ox…

Thus:

oxygen availability≠ oxygen delivery≠ mitochondrial access≠ oxygen processing≠ energetic utility.

This is very close to what we mean by impedance in the oxygen-delivery layer.

Indeed, the authors describe aging as deterioration in the ability to rapidly, locally, and reversibly match blood flow to metabolic demand.     

In impedance language, the problem is therefore not necessarily lack of oxygen upstream.

It is restricted flux through the pathway.

Carbon substrates face the same problem

Oxygen is only one side of oxidative metabolism.

Exactly the same principle applies to carbon substrates.

Glucose may be abundant.

Fatty acids may be abundant.

Stored triglycerides may be abundant.

Yet abundant substrate does not guarantee useful energy production.

Carbon must move through its own sequence:

availability → transport → cellular uptake → metabolic processing → mitochondrial entry → oxidation → electron transfer → ATP production.

Impedance can occur anywhere along that route.

Glucose can be abundant in circulation while cellular utilization is impaired.

Fatty acids can reach tissues but accumulate as ectopic lipid rather than being completely oxidized.

Carbon can enter mitochondria while downstream respiratory-chain or redox constraints restrict further throughput.

The result is an apparent paradox commonly encountered in metabolic disease:

resource abundance together with energetic stress.

This is why the distinction between supply and utility matters so much.

Increasing substrate supply when the processing pathway is already constrained may not improve energy production. It may instead increase congestion, storage, reactive intermediates, and compensatory stress.

Oxygen can behave similarly.

More oxygen does not automatically solve a microvascular, mitochondrial, or redox bottleneck.

Oxygenaging as an oxygen layer within a larger impedance architecture

This suggests a useful relationship between the two frameworks.

Oxygenaging can be regarded as a detailed description of one major physiological layer within the broader architecture of bioenergetic impedance.

The oxygen pathway can be simplified as:

atmosphere→ pulmonary exchange→ blood oxygen content→ cardiac delivery→ microvascular distribution→ tissue diffusion→ mitochondria.

The carbon-substrate pathway runs partly in parallel:

dietary or stored substrate→ circulation→ cellular uptake→ metabolic transformation→ mitochondrial entry→ oxidation.

Both ultimately converge on mitochondrial energetic processing.

But the convergence point itself can also become constrained.

Mitochondria must integrate oxygen, carbon substrates, reducing equivalents, membrane potential, respiratory-chain activity, redox balance, and ATP demand.

And the ATP produced must then support extraordinarily costly biological tasks: ion gradients, protein synthesis, proteostasis, detoxification, immune responses, tissue repair, DNA repair, and cellular remodeling.

Bioenergetic impedance therefore asks a broader question than whether oxygen or fuel is present:

Can the biological network actually move resources through the system at the rate required by current demand?

That is why Oxygenaging fits naturally as a specific impedance layer, rather than representing the whole impedance construct.

Acute adaptation can become chronic impedance

The Oxygenaging review becomes even more interesting when it moves from oxygen delivery to the cellular response.

During acute hypoxia, HIF signaling performs exactly what an adaptive system should do.

It reduces mitochondrial oxygen consumption.

It increases glycolytic dependence.

It suppresses energetically expensive anabolic activity.

It stimulates pathways intended to restore oxygen supply.

In the short term, this is protective.     

But aging appears to alter the ability to coordinate—and perhaps importantly, to terminate—these adaptations.

The authors describe impaired angiogenesis, reduced erythropoietic responsiveness, persistent pseudohypoxic signaling, mitochondrial quality-control failure, and a HIF-associated “lipid lock” that can contribute to prolonged lipid storage.     

This illustrates a broader principle that has been central to our recovery-dynamics thinking:

a process can be adaptive when transient yet maladaptive when it fails to resolve.

Temporary suppression of oxidative metabolism may preserve survival during acute hypoxia.

Persistent suppression becomes metabolic constraint.

Temporary lipid storage may protect against oxidative injury.

Persistent lipid trapping becomes metabolic burden.

Temporary stress signaling coordinates repair.

Persistent signaling can become part of the pathology itself.

In our terminology, adaptation can eventually become compensatory lock-in.

The most revealing measurement may be recovery

The skeletal-muscle section of the review provides an especially important clue.

Using phosphorus-31 magnetic resonance spectroscopy, younger muscle demonstrated a phosphocreatine recovery time constant of approximately 37 seconds, whereas older muscle required around 52 seconds.     

The importance of this observation goes beyond muscle.

It illustrates why resting measurements can miss early deterioration.

At rest, two individuals may appear quite similar.

Their oxygen saturation may be normal.

Their glucose may be acceptable.

Their ATP level may be maintained.

Their organ function may still fall within conventional reference intervals.

The difference appears after demand.

How rapidly can oxygen delivery increase?

How effectively can mitochondrial oxidation accelerate?

How much compensation is necessary to preserve function?

And once the challenge has ended:

How quickly does the system recover?

This is where dynamic physiology becomes much more informative than static biological age alone.

Aging may initially manifest not as inability to respond, but as slower recovery and progressively greater energetic cost required to maintain the response.

From impedance to unresolved backlog

This also connects Oxygenaging to the idea of recovery backlog.

A physiological challenge increases demand.

If sufficient throughput is available, the system responds, resolves the challenge, and returns toward its prior state.

But if energetic throughput is constrained, adaptation persists longer.

Now imagine that another challenge arrives before the previous response has fully resolved.

The next response begins from an altered starting point.

Repeated over time, incomplete resolution can generate a growing backlog of unresolved adaptation.

Oxygen-delivery impedance can contribute to that backlog.

Carbon-substrate processing impedance can contribute another layer.

Mitochondrial quality-control failure, inflammatory activity, proteostatic demands, environmental exposures, endocrine stress, and tissue repair may add further demands.

The crucial variable therefore becomes the relationship between:

incoming demandandthe capacity to resolve that demand.

Once the backlog approaches or exceeds available reserve, compensation becomes increasingly persistent and eventual decompensation becomes more likely.

Beyond individual hallmarks

The authors are appropriately cautious about positioning Oxygenaging.

They do not propose replacing the Hallmarks of Aging. Instead, they suggest that oxygen homeostasis constitutes a physiological axis through which mitochondrial dysfunction, inflammation, epigenetic alteration, altered nutrient sensing, cellular senescence, and other aging mechanisms can interact.     

We think this is where the emerging conceptual convergence becomes especially important.

The Hallmarks framework has been enormously valuable for identifying what changes during aging.

But the next stage of geroscience may increasingly need to explain:

Why do these processes become connected?

Why does compensation become progressively more expensive?

Why does recovery slow?

Why do adaptive responses eventually persist after the original challenge has disappeared?

Oxygenaging answers part of this through loss of oxygen homeostasis.

Bioenergetic impedance asks the same type of question across oxygen, carbon substrates, mitochondrial processing, redox constraints, and other energetic pathways.

Recovery dynamics then asks what happens over time when those constraints are repeatedly challenged.

These perspectives are not identical.

But they increasingly seem to occupy neighboring levels of the same emerging systems picture.

A different way to think about aging

This leads to a different set of questions for longevity science.

Instead of asking only:

How much oxygen is present?

we might ask:

Can it reach the tissue when demand increases?

Instead of asking:

How much glucose or fat is available?

we might ask:

Can it be processed and converted into useful energy?

Instead of asking:

Does the person still maintain function?

we might ask:

How much compensatory cost is required to preserve that function?

And instead of measuring only biological state, we may increasingly need to ask:

How quickly and completely does the system recover after perturbation?

Someone may have abundant metabolic fuel yet remain energetically constrained.

Someone may have normal arterial oxygen saturation while local oxygen delivery is impaired.

Someone may maintain apparently normal function while paying an increasingly large adaptive cost.

And two people with similar chronological—or even similar estimated biological—age may therefore possess very different capacities to withstand the next challenge.

The Oxygenaging review provides an important physiological piece of this emerging picture.

It demonstrates in considerable detail that:

Oxygen availability is not oxygen utility.

Carbon substrates follow the same principle.

Our already-published bioenergetic impedance perspective provides a broader formulation:

Energetic resources must not merely be present. They must be delivered, processed, converted into useful biological work, and supported by sufficient capacity for the system to recover after demand subsides.

Seen this way, Oxygenaging may represent the oxygen-delivery and oxygen-utilization layer of a wider bioenergetic impedance architecture, while carbon-substrate handling represents another major layer.

The fact that these frameworks have emerged independently—and that Ferrucci and colleagues are now explicitly framing oxygen physiology around resilience, supply–demand matching, and loss of reserve—suggests something larger may be happening in geroscience.

The field may be moving from cataloguing the components of aging toward understanding the dynamics that connect them.

And one of the most important transitions in aging may occur well before overt dysfunction:

when resources remain available, adaptation still preserves function, but throughput has become constrained and recovery is no longer complete.

Reference: 

Donega, S., Fishbein, K. W., Dominelli, P., Herman, A. B., de Cabo, R., Gorospe, M., & Ferrucci, L. (2026). Oxygenaging: A physiological framework for geroscience. Aging Cell, 25, e70664.