Gut microbiota-fatty acid oxidation interplay in aging: Mechanisms, controversies, and translational perspectives

Abstract

Aging is increasingly recognized as a systemic process shaped by metabolic adaptation and gut microbiota remodeling. While microbial dysbiosis has been linked to chronic inflammation and metabolic disorders, the mechanisms connecting microbiota changes to cellular senescence remain incompletely defined. Fatty acid oxidation (FAO), a central pathway in mitochondrial energy metabolism, has emerged as a context-dependent metabolic node linking microbial function to host metabolic decline. Recent studies suggest that age-associated microbiota remodeling is accompanied by enrichment of microbial FAO-related pathways, whereas microbiota-derived metabolites, including short-chain fatty acids and bile acids, may influence host lipid utilization and mitochondrial function. However, the causal directionality of these interactions and their physiological relevance remain uncertain. This opinion review synthesizes current evidence linking gut microbiota remodeling to FAO during aging, examines competing mechanistic interpretations, highlights key controversies, and outlines future directions for mechanistic and translational research.

Key Words: Aging; Gut microbiota; Fatty acid oxidation; Mitochondrial metabolism; Short-chain fatty acids; Bile acids; Metabolic senescence; Healthy aging

Core Tip: Gut microbiota remodeling during aging may influence fatty acid oxidation through microbial metabolites and host signaling pathways. This opinion review highlights fatty acid oxidation as a context-dependent metabolic node linking microbiota changes to aging phenotypes, while emphasizing unresolved causality, tissue specificity, and the need for integrated metabolic validation.

INTRODUCTION

Aging is no longer viewed simply as the gradual accumulation of molecular damage. It is increasingly recognized as a systems-level process in which metabolic, immune, and microbial alterations evolve in parallel[1,2]. Among these processes, metabolic reprogramming has emerged as a central feature, as changes in substrate utilization and mitochondrial efficiency occur early and propagate across multiple organ systems[3,4]. In parallel, the gut microbiota has gained recognition as a key regulator of host physiology, influencing immune tone, energy balance, and metabolic homeostasis throughout the lifespan[5,6].

Accumulating evidence indicates that the composition and functional capacity of the gut microbiota shift with age, often in association with metabolic decline and chronic low-grade inflammation[7-9]. Notably, studies of healthy aging and centenarian populations suggest that microbial functional profiles, rather than taxonomic composition alone, may better reflect physiological resilience[10,11]. These observations have shifted attention from descriptive dysbiosis toward microbiota-driven metabolic signaling.

Against this background, fatty acid oxidation (FAO) emerges as a plausible mechanistic interface. As a core mitochondrial pathway, FAO links energy production, redox balance, and cellular stress responses, all of which are tightly connected to aging biology[3,12]. Microbiota-derived metabolites, particularly short-chain fatty acids (SCFAs) and bile acids (BAs), are now recognized as important regulators of host metabolic signaling[13,14]. Taken together, these findings support the idea that microbiota remodeling may intersect mechanistically with FAO. However, whether this relationship reflects a causal pathway, an adaptive response, or parallel features of aging remains unresolved. Addressing this question requires integrating microbiome data with host metabolic measurements and distinguishing microbial functional potential from host metabolic flux. Figure 1 summarizes the proposed framework linking gut microbiota remodeling, microbial metabolites, host metabolic regulation, and FAO in aging.

Figure 1 Proposed framework linking gut microbiota remodeling to host metabolic regulation and fatty acid oxidation in aging. Aging is associated with gut microbiota remodeling, accompanied by altered microbial metabolites, including short-chain fatty acids, secondary bile acids, and lipid-derived signals. These changes may interact with host metabolic regulation, including AMP-activated protein kinase, farnesoid X receptor, Takeda G protein-coupled receptor 5, and mitochondrial function, thereby influencing fatty acid oxidation. Altered fatty acid oxidation may in turn contribute to aging-related phenotypes, including metabolic inflexibility, oxidative stress, and cellular senescence. The author used artificial intelligence tools to assist in the generation of graphical content included in this manuscript. All artificial intelligence-generated images were reviewed, verified, and approved by the author, who takes full responsibility for the accuracy, originality, and integrity of the final content.

GUT MICROBIOTA REMODELING ACROSS AGING

Aging is accompanied by reproducible yet heterogeneous shifts in gut microbial ecology. Although a decline in diversity is often reported, the more informative changes may occur at the functional level rather than at the level of taxonomy alone[15-18]. Systematic and narrative reviews consistently show that aging is associated with instability of microbial communities, depletion of beneficial commensals, and enrichment of taxa linked to frailty, inflammation, and metabolic dysfunction[15-18]. At the same time, the magnitude and direction of these changes vary across cohorts, indicating that aging-related microbial signatures are strongly shaped by diet, geography, medication exposure, and overall health status[18-21].

Studies of exceptionally long-lived populations have added an important nuance to this picture. Rather than simply preserving a younger microbiota, centenarians appear to harbor microbial communities with distinct functional features, including enrichment of pathways involved in BAs and lipid metabolism[10,11,19]. These observations suggest that microbial resilience in aging may be better understood in terms of metabolic capacity than by compositional similarity alone.

This distinction matters because changes in taxonomy do not necessarily translate into predictable biological output. Aging-related microbiota remodeling is increasingly viewed as a process of functional reorganization, with altered profiles of SCFAs, BAs, and other metabolites likely serving as the biologically active interface between the microbiota and the host[17,18,22]. Such functional remodeling offers a more concrete route by which gut ecology could influence host substrate utilization, mitochondrial activity, and metabolic stress.

FAO IN AGING BIOLOGY

FAO is a central component of mitochondrial energy metabolism, particularly in tissues with high and sustained energetic demand, such as the heart, liver, and skeletal muscle[3,23]. By converting fatty acids into acetyl-CoA and reducing equivalents, FAO supports oxidative phosphorylation and helps maintain metabolic flexibility under varying nutrient conditions[13,24]. In physiologic settings, this pathway is essential for preserving cellular energy balance and preventing ectopic lipid accumulation.

With aging, this metabolic balance becomes harder to maintain. Mitochondrial function declines, oxidative capacity is reduced, and the ability to match substrate supply with energy demand becomes less efficient[3,23,25]. In metabolically active tissues, this decline may shift substrate utilization away from coordinated oxidative metabolism and toward states of either lipid overload or maladaptive compensation. As a result, impaired FAO is often associated with lipid accumulation, reduced metabolic flexibility, and increased susceptibility to cellular stress[24-26].

At the same time, FAO cannot be viewed simply as a pathway that becomes uniformly deficient with age. Recent work suggests that excessive or dysregulated FAO may also be detrimental, particularly when mitochondrial quality control is compromised[12,27]. Under these conditions, sustained FAO can increase mitochondrial burden, enhance reactive oxygen species generation, and contribute to stress responses linked to senescence[12,27]. In this sense, FAO appears to operate within a narrow physiological window: Insufficient FAO favors lipid overload and energetic failure, whereas maladaptive or excessive FAO may promote oxidative injury.

This duality complicates any simple interpretation of microbiota-host metabolic crosstalk in aging. If microbiota-derived signals alter substrate selection or mitochondrial efficiency, the downstream consequences of FAO will likely depend on tissue context, mitochondrial integrity, and inflammatory state rather than on FAO activity alone. For that reason, FAO is better viewed as a context-dependent regulator of metabolic aging rather than as a uniformly protective pathway. Figure 2 highlights the context-dependent effects of FAO in aging, emphasizing that both insufficient and maladaptive increases in FAO may contribute to aging-related decline.

Figure 2 Context-dependent effects of fatty acid oxidation in aging. Reduced fatty acid oxidation (FAO) favors lipid accumulation, metabolic inflexibility, and energetic failure, whereas excessive or dysregulated FAO may increase mitochondrial burden, oxidative stress, and senescence-related signaling. These opposing effects indicate that FAO must be tightly regulated to preserve metabolic homeostasis during aging. The author used artificial intelligence tools to assist in the generation of graphical content included in this manuscript. All artificial intelligence-generated images were reviewed, verified, and approved by the author, who takes full responsibility for the accuracy, originality, and integrity of the final content.

MICROBIOTA-DERIVED MEDIATORS LINKING GUT ECOLOGY TO FAO

No single pathway is likely to explain how the gut microbiota influences host FAO. Instead, multiple layers of metabolic communication appear to be involved, with microbial metabolites acting as the principal intermediaries between gut ecology and host energy metabolism[28,29]. This shift in perspective places less emphasis on taxonomy alone and more on the biochemical outputs generated by the microbiota.

Among these mediators, SCFAs remain the best-characterized. Produced through bacterial fermentation of dietary fiber, acetate, propionate, and butyrate can influence host metabolism both as substrates and as signaling molecules[30,31]. Their effects extend beyond the intestinal lumen and include modulation of hepatic substrate selection, mitochondrial function, and systemic energy balance[30-32]. Importantly, SCFAs can activate signaling pathways such as AMP-activated protein kinase, thereby influencing lipid utilization and oxidative metabolism in peripheral tissues[30,31]. In the context of aging, reduced abundance of SCFA-producing taxa may therefore contribute to metabolic inflexibility rather than simply reflecting microbial drift.

BAs provide another major interface between the microbiota and host FAO. Primary BAs synthesized in the liver are transformed by gut microbes into secondary BAs with distinct signaling properties[33-35]. These microbial modifications influence host receptors such as the farnesoid X receptor and Takeda G protein-coupled receptor 5, both of which regulate lipid handling, mitochondrial activity, and energy expenditure[33]. Because these pathways operate at the intersection of nutrient sensing and metabolic regulation, altered BA pools in aging may have consequences that extend well beyond intestinal physiology.

A broader range of microbiota-derived metabolites may also shape FAO indirectly through inflammatory tone, insulin sensitivity, and substrate availability[28,35]. This is particularly relevant in aging, where metabolic stress rarely occurs in isolation. Instead, mitochondrial efficiency, redox balance, and inflammatory signaling interact continuously, meaning that the downstream impact of microbial metabolites on FAO is likely to be tissue-specific and context-dependent. Taken together, these observations suggest that FAO is better regarded as a metabolic node integrating diverse microbiota-derived signals rather than as a simple downstream effector. Table 1 summarizes the principal microbiota-derived mediators that may connect gut microbiota remodeling to host FAO during aging.

Table 1 Microbiota-derived mediators potentially linking gut microbiota remodeling to fatty acid oxidation during aging.

Mediator	Microbial source or pathway	Major host targets	Proposed link to fatty acid oxidation	Relevance to aging	Ref.
Short-chain fatty acids	Fermentation of dietary fiber by commensal bacteria	AMP-activated protein kinase, hepatic substrate utilization, mitochondrial metabolism	May influence substrate preference, improve metabolic flexibility, and modulate oxidative metabolism	Aging is often accompanied by reduced short-chain fatty acid production and loss of short-chain fatty acid-producing taxa	[13,30,31]
Secondary bile acids	Microbial transformation of primary bile acids	Farnesoid X receptor, Takeda G protein-coupled receptor 5, mitochondrial signaling	May reshape lipid handling, energy expenditure, and host oxidative metabolism	Centenarian-associated microbiota shows distinct bile acid-related functional signatures	[11,14,32,33]
Lipid-derived microbial signals	Microbiota-associated lipid processing and metabolite generation	Mitochondrial function, inflammatory tone, insulin sensitivity	May indirectly alter fatty acid oxidation through changes in redox balance and substrate availability	Likely contributes to tissue-specific metabolic remodeling during aging	[28,29,44,46]
Inflammatory mediators linked to dysbiosis	Barrier dysfunction, endotoxin exposure, altered microbial ecology	Immune-metabolic signaling, mitochondrial stress pathways	May shift host metabolism away from coordinated oxidative balance and promote maladaptive fatty acid oxidation responses	Chronic low-grade inflammation is a common feature of aging and microbial dysbiosis	[8,18,37,47]
Diet-microbiota interaction	Dietary fiber, fat quality, long-term dietary patterns	Microbial metabolite production, host substrate availability	May modify fatty acid oxidation indirectly by altering metabolite pools and nutrient flow	Especially relevant for translational strategies in older adults	[48-50,57]
Microbiota transfer or ecological manipulation	Fecal microbiota transplantation, microbiota-targeted interventions	Whole-body metabolic phenotype, tissue energetics	Useful for testing whether microbial states causally modify fatty acid oxidation-related phenotypes	Provides experimental leverage, but direct tissue-specific fatty acid oxidation effects remain insufficiently defined	[22,39,41,60]

EVIDENCE SUPPORTING THE MICROBIOTA-FAO-AGING AXIS

At present, evidence for a microbiota-FAO-aging axis is intriguing but still incomplete. Recent human cohort studies and experimental models indicate that age-associated microbiota remodeling is accompanied by broad changes in metabolic function, including pathways related to lipid metabolism and host aging phenotypes[9,10,36]. Their value lies in shifting the discussion away from broad descriptions of dysbiosis and toward specific metabolic functions that may become more prominent with age.

At the same time, such observations require careful interpretation. In most microbiome studies, microbial FAO refers to inferred enrichment of fatty acid degradation or β-oxidation gene modules derived from metagenomic annotation rather than direct biochemical measurement of microbial metabolic flux[37,38]. By contrast, host FAO reflects mitochondrial substrate utilization in tissues such as liver, heart, or skeletal muscle and is typically evaluated through enzymatic activity, metabolite tracing, or respiratory measurements[24,25]. Conflating these two levels can lead to overstatement of mechanistic conclusions.

Additional lines of evidence lend biological plausibility to this proposed axis. Age-related changes in microbiota composition have been linked to host lipid remodeling, altered BA pools, impaired mitochondrial function, and chronic inflammation[18,19,35,39]. Experimental manipulation of the microbiota can also shift systemic metabolic phenotypes, including tissue energetics and inflammatory tone, supporting the view that microbial ecology is not merely a passive correlate of aging[28,29,40]. More directly, transplantation studies indicate that age-associated microbiota can transmit aspects of the aging phenotype across host systems, although the specific role of FAO in these models remains incompletely resolved[39,41].

Pharmacologic studies provide another layer of support, but they also illustrate the limits of current evidence. Trimetazidine and related metabolic modulators are informative because they alter FAO and reveal links between substrate utilization, mitochondrial stress, and senescence-related pathways[40,42,43]. However, these interventions exert systemic effects that are not necessarily microbiota-dependent. For that reason, they should be interpreted primarily as mechanistic probes rather than direct proof that microbiota remodeling drives host FAO in aging. Overall, the available studies support the biological plausibility of this axis, although the strength of evidence still varies markedly across different levels of inference. At present, the field supports a working metabolic framework rather than a closed mechanistic chain.

CURRENT CONTROVERSIES AND LIMITATIONS

Despite increasing interest in the microbiota-FAO-aging axis, several conceptual and methodological challenges remain. The most fundamental unresolved issue is causality. Most current evidence is associative, drawing on cross-sectional human data, inferred functional annotation, or phenotypic changes observed after broad interventions[44,45]. While such studies are valuable for hypothesis generation, they do not resolve whether microbiota remodeling actively drives changes in host FAO or instead reflects host metabolic adaptation during aging.

A second challenge lies in the interpretation of microbial functional readouts. In many studies, pathway enrichment is inferred from metagenomic or metatranscriptomic data rather than measured directly at the level of flux or metabolite turnover[37,44]. This becomes particularly problematic when microbial fatty acid degradation pathways are discussed alongside host mitochondrial FAO, because these processes operate in different biological compartments and are not interchangeable. A more convincing causal framework will require microbiome sequencing to be integrated with isotope tracing, metabolomics, and tissue-specific assessment of oxidative metabolism.

A third limitation is tissue specificity. Aging is not metabolically uniform, nor is the impact of microbiota-derived signals[46,47]. The consequences of altered FAO in the liver, heart, skeletal muscle, adipose tissue, and brain may differ substantially depending on substrate preference, mitochondrial reserve, and inflammatory context. It is therefore unlikely that a single model will fully capture the role of FAO across all organ systems. This is particularly relevant when interpreting systemic interventions that may improve one tissue phenotype while worsening another.

Another unresolved issue concerns the directionality of metabolic change. Reduced FAO is often interpreted as pathological because it favors lipid accumulation and energetic failure. Yet, enhanced or sustained FAO may also be harmful when mitochondrial quality control is impaired, leading to increased oxidative burden and stress signaling[12,27]. In other words, both insufficient and maladaptive FAO may contribute to aging, depending on context. This duality complicates the search for simple interventional strategies and argues against viewing FAO as a uniformly beneficial target.

Finally, the current literature is marked by substantial heterogeneity in models, sequencing approaches, dietary context, and metabolite measurements[45,48]. Such variability makes direct comparison difficult and helps explain why some studies emphasize inflammation, others focus on BA signaling, and still others highlight mitochondrial dysfunction. At present, the field supports a plausible but still incomplete framework in which microbiota-derived signals intersect with FAO in aging. What is still lacking is an experimental strategy that can connect microbial function, host metabolic flux, and tissue-level aging phenotypes within the same system.

TRANSLATIONAL IMPLICATIONS

The translational appeal of the microbiota-FAO axis lies in its ability to connect modifiable environmental exposures, particularly diet and microbial ecology, with host metabolic pathways relevant to aging[49,50]. From a clinical perspective, this is important because microbiota-associated interventions are, at least in principle, more accessible and adaptable than many direct anti-aging strategies.

Diet is the most immediate entry point. Dietary fiber, fat quality, and overall dietary pattern shape the production of SCFAs, BAs, and other microbiota-derived metabolites that may influence host lipid handling and mitochondrial metabolism[48,51-53]. This makes nutritional intervention particularly relevant when considering FAO, as changes in substrate availability and microbial fermentation may converge on the same host metabolic pathways. In this regard, the microbiota-FAO axis may be especially useful as a framework for designing metabolism-oriented dietary strategies rather than as a narrowly defined microbial target.

Microbiota-directed therapies also warrant consideration. Probiotics, prebiotics, and fecal microbiota transplantation have all been investigated as tools to reshape microbial ecology and alter host metabolism[22,41,53]. However, the translational relevance of these approaches remains uneven. Effects are often context-specific, vary by baseline microbiota structure, and may not be durable over time. More importantly, the extent to which such interventions can modify host FAO in a meaningful and tissue-specific manner remains largely unknown.

Pharmacologic modulation represents another possible route, but it also illustrates the limits of current knowledge. Metabolic modulators such as trimetazidine are informative because they alter FAO and thereby reveal mechanistic links between substrate utilization, mitochondrial stress, and senescence-related pathways[42]. Yet, these observations should be interpreted primarily as mechanistic insights rather than direct evidence for anti-aging therapy. Systemic metabolic effects, tissue specificity, and the possibility of off-target consequences remain important constraints.

For now, the clearest translational value of this axis may lie in biomarker development and metabolic stratification rather than in intervention alone. Integrating microbiome signatures with metabolomics and host metabolic readouts could help identify subsets of older individuals in whom altered FAO is linked to specific microbial states[46,54]. Such an approach may ultimately prove more informative than attempts to define a single universal microbiota-based intervention for aging.

FUTURE DIRECTIONS

The field now needs to move beyond associative observations and toward experimental systems that can resolve directionality and mechanism. One priority is the integration of microbiome profiling with metabolomics and direct measurements of host substrate utilization. At present, sequencing-based pathway inference often outpaces functional validation. Linking microbial composition and metagenomic potential to actual metabolite production and tissue-specific FAO will therefore be essential[46,54,55].

A second priority is longitudinal design. Aging is a dynamic process, yet most current studies rely on cross-sectional sampling or short-term interventions. Repeated sampling across aging trajectories, ideally paired with dietary records, metabolic phenotyping, and clinical outcomes, will be necessary to distinguish stable microbial signatures from transient ecological fluctuations[56-58]. This is especially important because microbiota-associated metabolic effects are often highly individualized and may differ substantially by baseline microbial composition, host metabolic state, and habitual diet.

A third need is experimental causality. Gnotobiotic models, fecal microbiota transplantation, isotope tracing, and tissue-specific metabolic analysis should be combined rather than used in isolation[41,59,60]. Only such integrative designs will be able to determine whether specific microbial states alter host FAO directly, whether changes are mediated by metabolites, or whether both are secondary to broader shifts in host physiology. In parallel, future studies should account for tissue specificity, since the metabolic consequences of altered FAO are unlikely to be identical across the liver, heart, muscle, adipose tissue, and brain.

Finally, progress in this field will likely depend on moving away from single-pathway explanations and toward systems-level metabolic models. FAO may remain central within this framework, but its role will be best understood when analyzed together with inflammation, BA signaling, redox balance, and cellular senescence. In that sense, the most productive future direction is not simply to ask whether microbiota regulates FAO, but under what conditions, in which tissues, and with what consequences for aging phenotypes.

CONCLUSION

Current evidence suggests that gut microbiota remodeling and FAO intersect within a broader metabolic framework of aging. This relationship is biologically plausible, mechanistically attractive, and increasingly supported by converging data from microbiome research, metabolite profiling, and host metabolic studies[28,46,54]. At the same time, the field has not yet established a definitive causal chain linking microbial functional shifts to tissue-specific FAO changes and downstream aging phenotypes.

For this reason, FAO should not be viewed as a singular explanation for aging, nor should microbiota-targeted modulation of FAO be framed as an established anti-aging strategy. Rather, FAO is better understood as a context-dependent metabolic node through which microbiota-derived signals may intersect with mitochondrial stress, inflammatory tone, and metabolic resilience. Its main value is not that it provides a closed mechanism, but that it offers a testable model linking microbial ecology to host energy metabolism.

A more precise understanding of this axis will require studies that connect microbial function, metabolite production, host substrate flux, and tissue-specific outcomes within the same experimental system. If such links can be established, the microbiota-FAO interface may become a useful platform not only for understanding aging biology but also for identifying metabolically defined subgroups that are more likely to benefit from targeted nutritional, microbial, or pharmacologic interventions.