What we should know

• Cerebral glucose hypometabolism- a decline in the brain's ability to use its primary fuel— is increasingly recognised as a feature of ageing in both humans and dogs, independent of blood glucose availability

• Synaptelyn® was formulated around two converging mechanisms: an alternative substrate for cerebral energy production, and a signalling pathway linked to neuronal resilience and synaptic plasticity

"At heart, the core issue with the distressed canine brain is a metabolic problem; an energy mismatch"

As the brain ages, its capacity to take up and utilise glucose can decline, even where circulating glucose remains normal. This produces a progressive mismatch between neuronal energy demand and available supply:

• Neuronal energy requirements remain high across the lifespan

• Glucose utilisation efficiency declines

• Mitochondrial output is reduced

• Oxidative stress accumulates

• Synaptic maintenance becomes energetically harder to sustain

• Learning, memory, sleep-wake regulation and spatial orientation are affected downstream

Our active was designed to act upstream of these downstream effects, by addressing the metabolic conditions neurons operate under; rather than simply targeting or masking the behavioural symptoms directly. We explore these mechanisms below.

Mechanism one: an alternative substrate for cerebral energy production

Following ingestion, Synaptelyn's fractionated fatty-acid substrate is absorbed more directly than conventional long-chain dietary fats and transported largely to the liver, where beta-oxidation converts it into ketone bodies; principally beta-hydroxybutyrate and acetoacetate, with acetone present in smaller quantities.

These ketone bodies are proven to cross the blood-brain barrier via monocarboxylate transporters. Inside neurons, they are converted back to acetyl-CoA, entering the citric acid cycle and supporting:

• ATP production

• Maintenance of the membrane ion gradients required for neuronal firing

• Neurotransmitter synthesis and recycling

• Synaptic vesicle loading and release

• Ongoing cellular repair and protein turnover

Schematically the flow is 1. fatty-acid substrate > 2. hepatic beta-oxidation > 3 ketogenesis > 4. blood-brain barrier transport > 5. neuronal acetyl-CoA > 6. ATP.

This pathway doesn't restore glucose metabolism directly, but what it does do is provide the ageing brain with a second route to usable energy, one that can remain functional when glucose-derived energy production has become less reliable. It draws on the same broad principle that underlies medium-chain fat supplementation more generally, but the specific fractionation and the butyrate component below are where Synaptelyn's mechanism extends further.

Mechanism two: butyrate as a signal

At the concentrations present, it functions as a signalling molecule, largely via its inhibitory effect on histone deacetylase (HDAC) activity.

Gene accessibility is governed in part by histone acetylation state (eg how tightly DNA is packaged around its supporting histone proteins). Butyrate's inhibition of certain HDAC activity is associated with a more transcriptionally permissive chromatin state for genes linked to:

• Neuronal survival

• Cellular stress adaptation

• Synaptic remodelling

• Learning and memory

• Neurotrophic signalling

One relevant downstream pathway is brain-derived neurotrophic factor (BDNF), implicated in synaptic plasticity, memory consolidation, and neuronal survival under stress.

Butyrate exposure has been associated in experimental research with changes in neurotrophic and plasticity-related signalling, which is why we regard the butyrate component as potentially the more mechanistically significant half of Synaptelyn, rather than a second energy source layered onto the first.