In this review, we examine recent studies highlighting aging as the main risk factor for neurological disorders such as tauopathies. We discuss how preventing or reversing neuronal aging could represent a promising strategy for neuroprotection against these disorders. Finally, we briefly consider potential therapeutic approaches targeting proteins predominantly expressed in neurons, including folate receptor alpha (FRα), receptor for growth differentiation factor 15 (GDF15), and tau protein.

A recent study [1], using plasma proteomics, reported a connection between brain aging, health span, and longevity. By analyzing aging patterns across different human organs, the authors showed that individuals with relatively youthful brain profiles tend to exhibit greater longevity.

Although many differences exist between the brain and peripheral organs, we will focus on one key aspect: energy consumption. The brain represents only about 2% of total body mass but consumes approximately 20% of the body’s total energy [2].

Neurons, due to their high energy demands, rely primarily on mitochondrial oxidative phosphorylation. They have limited glycolytic capacity and preferentially use astrocyte-derived lactate, converting it into pyruvate for mitochondrial oxidation to generate the ATP required for synaptic transmission. Beyond the lactate shuttle, astrocytes regulate the tripartite synapse by clearing excess glutamate to prevent neurotoxicity, regulating extracellular potassium, and modulating synaptic plasticity. Furthermore, their end-feet control the blood–brain barrier (BBB), proving that neurons cannot survive or process information without this constant astrocytic support [3, 4]. Neuronal high-energy demand largely reflects neuronal communication at synapses, particularly at presynaptic [5] and mainly at postsynaptic sites [6]. Synaptic activity requires significant ATP consumption to restore ion gradients, recycle neurotransmitters, and maintain the resting membrane potential. ATP production occurs in mitochondria through oxidative metabolism, whereby carbohydrates and lipids are metabolized to generate ATP [7].

At the cellular level, aging in both the brain and peripheral organs leads to the accumulation of senescent cells [8]. Cellular senescence is characterized by a metabolic shift from OXPHOS to glycolysis, along with a disruption of this homeostatic equilibrium [9, 10]. Astrocyte senescence disrupts the Astrocyte-Neuron Lactate Shuttle, inducing a critical neuronal energy deficit that drives neurodegeneration. When astrocytes enter a senescent state due to aging or cellular stress, they undergo metabolic reprogramming. This shift compromises their ability to synthesize and transport lactate to neurons, starving synaptic networks of their primary fuel [10]. Additionally, aging is often associated with elevated glucose levels (hyperglycemia), which can induce neuronal damage through mitochondrial dysfunction [11]. However, folate and its receptor, FRα—predominantly expressed in neurons—may help mitigate such damage [12].

Because the aging brain requires large amounts of energy, it may draw resources from the rest of the body. The brain has therefore been described as a “selfish organ”, prioritizing its own energy needs while contributing to aging in peripheral tissues. In this context, the Martin-Picard group proposed the brain-body energy conservation model [13, 14]. According to this model, the brain plays a central role in regulating systemic energy allocation, maintaining its own energy supply by suppressing energy expenditure in other organs [13].

One of the earliest cellular processes observed in the AD brain is cell cycle reentry in neurons, that cell cycle reentry may be abortive, triggering neuronal cell death [15, 16]. However, a more explored field and possible underlying mechanism for cerebral aging involves cellular senescence (Figure 1). During aging, some cells stop dividing and enter senescence. As indicated above for neurons, senescence is an energetically costly process and is associated with the secretion of inflammatory factors, including cytokines, in different cell types. One such cytokine, GDF15, signals increased energy demand to the brain [17]. GDF15 is secreted by several aging organs, whereas its receptor (GFRAL) [18, 19] is expressed almost exclusively in the brain [20]. GDF15 does not need to cross the BBB to exert its metabolic effects because its receptor, GFRAL, is located exclusively within the circumventricular organs of the hindbrain. GDF15 activates GFRAL-expressing neurons localized exclusively in the area postrema and nucleus tractus solitarius of the mouse brainstem. It then triggers the activation of neurons localized within the parabrachial nucleus and central amygdala that shape feeding responses to stressful conditions [20]. The brain monitors these energetically demanding processes and compensates by reducing energy expenditure in peripheral functions that are not essential for survival, such as maximal heart rate, muscle mass, bone mass, and hair pigmentation [14].

Consistent with this systemic regulation, recent findings show that aging neurons produce elevated levels of WD repeat and FYVE domain-containing protein 1 (WDFY1). This protein can be transported from the brain to bone via extracellular vesicles, contributing to bone–fat imbalance and osteoporosis [21].

GDF15 is a mitochondrial-stress-responsive cytokine [14] that acts as a biomarker for aging and neurodegenerative diseases, often correlating with phosphorylated tau (p-tau) in cerebrospinal fluid. Elevated GDF15 levels are associated with increased neuroinflammation, higher levels of Tau pathology, and cognitive impairment [17, 22]. Under chronic stress conditions, peripheral signals can activate the amygdala [7, 23], which in turn stimulates the hypothalamus–pituitary–adrenal (HPA) axis. This communication from the periphery involves the brainstem region known as the nucleus tractus solitarius [24], which may play a broader role in integrating signals between the brain and peripheral organs.

Not all brain regions consume energy equally. Studies measuring energy distribution across the functional connectome have shown that evolutionarily expanded regions of the human brain, particularly the cortex, require up to 67% more energy than regions mainly involved in sensory-motor processing, such as the brainstem [25]. In other words, if the brain is divided into cortex, limbic system, and brainstem, the frontal-parietal cortex is the most energy-demanding region [25].

Interestingly, tau protein—primarily expressed in neurons [26]—is also particularly abundant in cortical areas [27, 28]. This observation suggests a possible relationship between age-related changes in functional brain networks [29] and age-dependent alterations in tau levels that may contribute to neurodegenerative diseases known as tauopathies [30].

In aging neurons, tau accumulation may result from reduced energy availability for processes such as protein turnover. When tau degradation decreases, the protein accumulates and can eventually form pathological aggregates [31]. This abnormal accumulation is also associated with the presence of senescent neurons [32].

As discussed above, aging is the main risk factor for tauopathies. Therefore, effective neuroprotective strategies should aim to prevent, delay, or reverse neuronal aging.

A pioneering study by Yamanaka and Takahashi [33] demonstrated that differentiated peripheral cells can be reprogrammed into induced pluripotent stem cells (iPSCs) with embryonic-like characteristics through the expression of four transcription factors known as the Yamanaka factors (YF).

Subsequent work using mouse models showed that permanent expression of YF may promote tumor formation [34]. However, cyclic expression of YF at controlled levels promoted rejuvenation of peripheral tissues such as pancreas, spleen, skin, and muscle [35]. When neurons in culture were induced to express YF continuously, reprogramming into iPSCs did not occur [36]. However, cyclic expression of YF resulted in neuronal rejuvenation [37].

Despite these promising findings, such approaches rely on genetic manipulation in mouse models and are not easily translated into clinical therapies in humans. Therefore, efforts have been made to identify small molecules capable of reproducing similar rejuvenating effects.

In this context, the Izpisua-Belmonte laboratory described a cocktail of four compounds, including methionine (a one-carbon metabolism metabolite), that induced partial cellular reprogramming in non-neuronal cells [38]. Using a similar approach, rejuvenation of neural cells was later demonstrated [39]. However, an important improvement was achieved when methionine was replaced by folate [40].

Folate receptor is a glycosyl-phosphatidylinositol-bound membrane protein that mediates the cellular uptake of folate and the related coenzymes. Ligand binding to folate receptors stimulates their endocytic uptake by a clathrin-independent pathway [41]. Once internalized into endosomes, the acidic pH of the lysosome causes dissociation of folate; the receptor is transported to the cell nucleus [42], where it acts as a transcription factor regulating oncogenic genes and facilitating the expression of the so-called YF [43], and leading to neuronal rejuvenation [40, 42]. In addition, FRα functions via non-canonical signaling mechanisms: it physically associates with GP130 to activate the JAK-STAT3 pathway and triggers the ERK1/2 cascade [44].

Thus, neuronal rejuvenation may represent a promising strategy for neuroprotection against neurodegenerative diseases.

However, folate and its derivatives participate in many cellular pathways, and high doses may produce undesirable side effects. Consequently, researchers have searched for small molecules capable of mimicking folate activity through interaction with FRα.

A small FRα-binding peptide with functions similar to folate was first described some years ago [45]. More recently, a family of FRα-binding peptides with similar properties has been identified [46]. Importantly, these peptides can cross the BBB and may therefore be delivered through peripheral administration [46].

Figure 2 summarizes the mechanism by which these FRα-binding peptides promote neuronal rejuvenation.

Here we briefly discuss several therapeutic strategies currently being tested in cellular and animal models, with only a few approaches at a very early clinical stage.

As noted in the Introduction, aging is the main risk factor for neurological disorders and is strongly associated with decreased cellular energy levels due to mitochondrial dysfunction. Therefore, we will mainly focus on therapies aimed at preventing or reversing aging processes rather than lifestyle interventions such as exercise or dietary modifications [47], although such approaches may also delay aging—for example through the use of vitamin B cofactors involved in mitochondrial ATP production.

Nevertheless, it is worth briefly noting the role of lifestyle factors and circulating molecules that may regulate brain aging. Recent studies have shown that the liver-derived exercise factor GPLD1 (exerkine) targets glycosylphosphatidylinositol (GPI)-anchored proteins on the vasculature of the aging brain. Increased levels of GPLD1 have been associated with rejuvenation of the BBB and a reduction in pathological aging processes [48].

As mentioned above, GDF15 is a stress-induced cytokine that regulates metabolism, inflammation, and tissue repair, primarily by acting as a natural appetite suppressor via the GFRAL receptor. Elevated GDF15 levels are associated with various diseases, acting as a biomarker and therapeutic target for cancer cachexia, obesity, cardiovascular disease, and severe morning sickness. Thus, several clinical trials are actually ongoing (https://clinicaltrials.gov/search?term=GDF15). In addition, physical exercise promotes the secretion of irisin, a peptide derived from the FNDC5 protein, primarily released by skeletal muscle. Once in circulation, irisin can cross the BBB and has been shown to facilitate the clearance of damaged neuronal mitochondria through mitophagy. It may also induce the expression of brain-derived neurotrophic factor (BDNF). Together, these processes contribute to neuronal rejuvenation and improved brain function [49, 50].

In summary, based on these previous comments, potential therapeutic strategies include:

Maintaining cellular energy levels

Given the rapid progress in this field, it is likely that additional strategies will emerge in the near future.

In this review, we have briefly explored the role of aging in neurodegeneration, emphasizing the exceptionally high energy demands of both healthy and aging brains, particularly in the presence of accumulating senescent neurons.

Mitochondria play a central role in meeting these energy requirements. Notably, the three neuronal proteins highlighted in this mini-review—FRα [64], GDF15 [65] and tau [66–68]—are closely linked to mitochondrial function and dysfunction.

We propose that delaying neuronal aging or promoting the rejuvenation of adult neurons before they enter senescence may represent effective neuroprotective strategies. Finally, we have discussed several emerging therapeutic approaches aimed at preventing neuropathological aging and associated neuronal disorders.