The Ageing Adipose Paradox: Implications for Metabolic Health

ABSTRACT

Background

Preadipocyte commitment to the adipogenic lineage declines markedly with advancing age, while triglyceride accumulation in hypertrophied existing adipocytes persists or expands. This creates a dissociation between adipogenic capacity and lipid‐buffering demand, progressively weakening depot metabolic competence and contributing to systemic insulin resistance.

Objective

This review examines the molecular mechanisms linking impaired adipose tissue plasticity during ageing to metabolic decline, and appraises therapeutic strategies that may restore adipose progenitor competence or limit downstream metabolic dysfunction.

Key Findings

Ageing adipose tissue is characterized by four interlocking defects. First, transcriptional reprogramming, including induction of the inhibitory CCAAT/enhancer‐binding protein β‐LIP isoform through CUG triplet repeat‐binding protein 1, together with reduced C/EBPα and peroxisome proliferator‐activated receptor γ activity, shifts progenitors away from differentiation and toward hypertrophic lipid storage. Second, SIRT7 opposes SIRT1 in regulating adipogenic commitment, implicating sirtuin and NAD⁺ dysregulation in the age‐related adipogenic deficit. Third, nuclear lamina remodelling restricts chromatin accessibility at adipogenic loci. Fourth, senescent cells accumulate in ageing depots and generate a senescence‐associated secretory phenotype enriched in interleukin‐6, tumour necrosis factor‐α, and matrix metalloproteinases, sustaining local inflammation and inhibiting preadipocyte differentiation. These changes occur alongside redistribution of fat from subcutaneous depots toward visceral, hepatic, muscular, and perivascular compartments, accelerating insulin resistance, Type 2 diabetes, and cardiovascular disease. Sex‐specific depot trajectories diverge, and rodent models reproduce these patterns only partly.

Therapeutic Implications

Senolytics, NAD⁺ precursors, and incretin‐based agents, including GLP‐1 and dual GIP/GLP‐1 receptor agonists, are reviewed together with still‐preclinical stem cell and CRISPR approaches, ranked by translational readiness.

Conclusion

Restoring adipose progenitor competence while preserving depot‐specific metabolic identity may help slow age‐related metabolic deterioration and prolong healthspan.

List of Abbreviations

ADSC

adipose‐derived stem cell

AMPK

AMP‐activated protein kinase

ATF4

activating transcription factor 4

BAT

brown adipose tissue

BCL‐2

B‐cell lymphoma 2

BMR

basal metabolic rate

C/EBP

CCAAT/enhancer‐binding protein

CHOP

C/EBP homologous protein

CRISPR

clustered regularly interspaced short palindromic repeats

CVD

cardiovascular disease

FOXO1

forkhead box O1

GIP

glucose‐dependent insulinotropic polypeptide

GLP‐1

glucagon‐like peptide‐1

HDAC

histone deacetylase

HFD

high‐fat diet

HGPS

Hutchinson‐Gilford progeria syndrome

IGF‐1

insulin‐like growth factor 1

IL

interleukin

iPSC

induced pluripotent stem cell

JAK/STAT

Janus kinase/signal transducer and activator of transcription

LMNA/C

lamin A/C

LPS

lipopolysaccharide

MACE

major adverse cardiovascular events

MKRN1

makorin ring‐finger protein 1

mTOR(C1)

mechanistic target of rapamycin (complex 1)

NAD⁺

nicotinamide adenine dinucleotide

NAMPT

nicotinamide phosphoribosyltransferase

NF‐κB

nuclear factor kappa B

NMN

nicotinamide mononucleotide

NR

nicotinamide riboside

NRIP1

nuclear receptor‐interacting protein 1

PARP‐1

poly(ADP‐ribose) polymerase 1

PPARγ

peroxisome proliferator‐activated receptor‐γ

RS

replicative senescence

SASP

senescence‐associated secretory phenotype

SAT

subcutaneous adipose tissue

SIPS

stress‐induced premature senescence

SIRT

sirtuin

SPM

specialised pro‐resolving mediator

T2DM

type 2 diabetes mellitus

TGF‐β

transforming growth factor‐β

TNF‐α

tumour necrosis factor‐α

TSA

trichostatin A

UCP1

uncoupling protein 1

VAT

visceral adipose tissue

WAT

white adipose tissue

1. The Ageing Adipose Paradox

Energy storage, substrate flux and endocrine output all route through adipose tissue, the principal integrator of systemic metabolic homeostasis [1]. By the fourth decade, this regulation measurably falters. Lipid trafficking and adipogenic transcription at C/EBPα and PPARγ loci deteriorate independently but cooperatively [2]. Senescent cell accumulation and reordered adipokine secretion add a systemic inflammatory dimension. Distinct effectors operate in each pathway, but hepatic and peripheral insulin resistance is the shared outcome. Chronic low‐grade inflammation in ageing depots becomes self‐sustaining, persisting independently of any identifiable initiating stimulus. Insulin sensitivity declines at muscle, liver and vascular targets.

Fat accumulates even as adipogenesis declines, and subcutaneous adipose tissue (SAT) plasticity is the first to fail. Once SAT expandability is exhausted, surplus lipid spills ectopically into liver parenchyma, skeletal muscle and perivascular and pericardial beds, where organ‐specific insulin resistance arises at each site [3]. Brown and beige fat thermogenic output contracts in parallel. Adrenergic sensitivity falls and mitochondrial uncoupling capacity contracts as sex‐steroid concentrations decline [4].

When sirtuin deacetylase activity, nuclear lamin integrity and C/EBP family expression are concurrently disrupted, adipocyte transcriptional reprogramming converts functional storage cells into dysfunctional secretory phenotypes. C/EBPα and PPARγ loci are primary targets. Age‐dependent chromatin remodelling at these loci progressively suppresses adipogenic commitment in progenitors, and adipose ageing is now recognised as a metabolic risk determinant spanning cardiovascular, endocrine and hepatic systems.

Three mechanistic questions remain open. Whether senescence drives adipose dysfunction, or whether metabolic stress precipitates senescent conversion before replicative exhaustion, is unresolved. Depot‐specific and sex‐dependent ageing trajectories carry distinct disease risks yet remain incompletely mapped, particularly outside European populations. No pharmacological or genetic intervention targeting these mechanisms has cleared Phase III evaluation. This review synthesises mechanistic advances across four axes and appraises the pharmacological and genetic strategies targeting each: senescence and the SASP, sirtuin–NAD⁺ signalling, lamina‐ and C/EBP‐driven transcriptional reprogramming, and progenitor exhaustion. Open questions in depot biology and the translational barriers from mechanism to clinic are taken up in the closing sections.

1.1. Adipocyte Subtypes and the Thermogenic Axis

White adipocytes store triglyceride, whereas brown and beige counterparts oxidise it through uncoupling protein 1 (UCP1), which dissipates the mitochondrial proton gradient as heat rather than coupling it to adenosine triphosphate (ATP) synthesis [5, 6]. After midlife, UCP1 promoter methylation rises and sympathetic innervation of brown depots recedes [7, 8]; catecholamine‐stimulated lipolysis in aged white adipocytes contracts in parallel as adrenergic tone falls [9]. Interleukin‐6 (IL‐6), tumour necrosis factor‐α (TNF‐α) and monocyte chemoattractant protein‐1 (MCP‐1) secretion climbs as these functions wane [10].

1.2. The Central Paradox

Fat storage persists, and even accelerates, as the capacity to generate functional adipocytes declines 1. C/EBPα and PPARγ expression falls at both subcutaneous and visceral loci, curtailing competent adipogenesis and diverting surplus lipid into unilocular droplets that distend beyond physiological storage capacity [11]. Endoplasmic reticulum stress ensues in these hypertrophied cells, and p16INK4a‐positive cells elaborate a SASP whose paracrine C/EBPβ and PPARγ suppression in adjacent progenitors arrests replacement adipogenesis. Macrophage infiltration into crown‐like structures sustains local inflammation and fibrosis [12, 13] (Figure 1).

FIGURE 1.

Age‐dependent Modulation of Adipogenic Capacity and Lipid Accumulation Across the human lifespan. Three phases of adipogenic capacity and lipid handling span human development. In early life (infancy to adolescence), developmental transcription factors and hormones (IGF‐1, insulin, thyroid) sustain high adipogenic potential and lipid absorption. Adipogenic rate and lipid accumulation stabilise through adulthood. After midlife, adipogenic capacity falls while lipid uptake persists, accompanied by senescence, chronic inflammation, disrupted adipokine balance (leptin/adiponectin), declining sirtuin activity and ECM remodelling; ectopic fat accumulation and metabolic dysfunction result.

1.3. Sirtuin Balance

The three nuclear sirtuins (SIRT1, SIRT6 and SIRT7) require nicotinamide adenine dinucleotide (NAD⁺) as an obligate cofactor [14]. Cellular NAD⁺ pools fall after midlife. SIRT1 deacetylates forkhead box O1 (FOXO1) and redirects adipocyte lipid metabolism from storage toward lipolysis. SIRT7 opposes SIRT1 at PPARγ target promoters, instead promoting adipogenesis. SIRT6 provides context‐dependent counter‐regulation. Adipose plasticity tracks the SIRT1:SIRT7 ratio, not the total sirtuin pool. Because SIRT1 and SIRT7 exert opposing transcriptional effects at PPARγ target loci, pan‐sirtuin activation cannot restore adipose metabolic homeostasis in ageing. Therapy must therefore restore NAD⁺ supply and recalibrate the SIRT1:SIRT7 ratio rather than maximally activate the family.

1.4. Depot Redistribution

Adipocyte hypertrophy develops paradoxically in ageing depots as adipogenesis and progenitor recruitment both decline [1, 15]. In parallel, fat redistributes from SAT to visceral adipose tissue (VAT). Subcutaneous and visceral progenitor biology diverges sharply. Gluteofemoral SAT buffers postprandial lipid and retains high adipogenic capacity, properties that provide metabolic protection even in mild obesity. VAT progenitors derive in part from a mesothelium‐associated lineage, and both adipogenic competence and replicative senescence timing differ from their subcutaneous counterparts. Senescent visceral adipocytes release palmitate, IL‐6 and TNF‐α directly into the portal circulation [16]; hepatic exposure to these mediators is therefore continuous. Once SAT expandability is exhausted, surplus lipid accumulates in liver, skeletal muscle and perivascular tissue, and organ‐specific insulin resistance develops at each ectopic site [17] (Figure 2). Interrupting ectopic lipid overflow and portal inflammatory flux requires both clearance of senescent visceral adipocytes and preservation of subcutaneous depot integrity.

FIGURE 2.

Dynamic alterations in adipose tissue distribution during ageing in women. Age‐related shifts in female fat depot distribution with ageing. In young adult women (~28 years), subcutaneous adipose tissue predominates (shown by yellow stippling), with metabolically favourable characteristics. By mid‐life (~50 years), fat redistribution begins with progressive visceral adipose accumulation (pink stippled regions) and early ectopic lipid infiltration. In advanced age (> 70 years), pronounced visceral adiposity predominates, accompanied by extensive ectopic fat infiltration (solid yellow areas in liver and muscle). Oestrogen decline after menopause accelerates this redistribution. Cardiometabolic risk and tissue‐specific pathology rise in parallel. Source: Adapted from Guo et al. [15].

1.5. Sexual Dimorphism

Fat‐depot ageing follows sexually dimorphic trajectories. Oestrogen‐receptor isoform expression, transcriptional activity and ligand sensitivity all vary with chronological age, biological sex and depot origin, and together govern the divergent remodelling programmes of the subcutaneous and visceral compartments [18, 19]. At menopause, fat redistribution shifts from gynoid to android, and central adiposity accelerates [20]. In men, visceral fat accrual begins earlier and tracks declining testosterone [21]. Genome‐wide association studies (GWAS) provide genetic reinforcement: fat‐distribution loci show stronger associations in women than in men [22]. Sex, age and depot interact to set cardiometabolic risk.

1.6. Species Differences

The adipogenic ageing trajectory is not conserved across species. Human adipose‐derived stromal/progenitor cells retain differentiation competence under sustained lipotoxic and glucotoxic challenge, whereas murine counterparts undergo accelerated senescent conversion at equivalent metabolic load [23]. Human and murine adipose progenitors also differ in age‐dependent mitochondrial oxidative capacity, cristae remodelling kinetics and the cis‐regulatory enhancer architecture governing adipogenic commitment, differences that constrain the translational fidelity of rodent models [24]. Several human regulatory progenitor subpopulations identified by single‐cell profiling are under‐represented in murine datasets. Cross‐species white‐adipose atlases show that major cell classes are conserved, but most interspecies variation reflects quantitative differences in shared progenitor populations rather than differences in lineage composition [16]. Translational models therefore require species‐specific calibration.

1.7. Convergent Molecular Alterations

CUGBP1‐mediated post‐transcriptional upregulation drives C/EBPβ‐LIP isoform accumulation across both subcutaneous and visceral ageing depots, and C/EBPα expression declines in parallel [25]. Adipocyte hypertrophy consequently supplants progenitor‐driven hyperplastic expansion as the predominant mode of depot growth, while senescent cell burden accumulates progressively across both subcutaneous and visceral compartments; the resulting SASP is sustained and amplified through combined activation of NF‐κB, C/EBPβ and JAK/STAT signalling cascades within the stromal‐vascular fraction [26] (Table 1). Chronic low‐grade inflammation in aged adipose becomes self‐sustaining as a result.

TABLE 1.

Key mechanisms and clinical implications of adipose tissue ageing. Summary of major findings across the lifespan, including early‐life programming and late‐life changes. Ageing is characterised by reduced adipogenic capacity, senescent‐cell accumulation, pro‐inflammatory SASP signalling, depot redistribution and transcriptional dysregulation of C/EBP and sirtuin pathways. The net effect is ectopic fat deposition, insulin resistance and systemic inflammation. Species‐specific differences between murine and human adipose biology impose translational limitations [1, 9, 10, 27].

Life stages	Aspects	Key findings	Molecular mechanisms	Clinical implications
Early life	Developmental programming	Begins in utero Influenced by genetics, hormones, and environmental factors Early nutrition critically impacts adipocyte proliferation	Responsive gene expression Modifications in lipogenesis, protein synthesis, and insulin sensitivity	Long‐term metabolic programming ↑ obesity risk later in life
Late life	Adipogenic capacity	4Paradoxical ↓ in adipogenesis ↑ Lipid accumulation in existing adipocytes	3Reduced C/EBPα and PPARγ expression Impaired preadipocyte differentiation Enhanced lipid uptake mechanisms	3Ectopic fat deposition Altered metabolic capacity
	Cellular senescence	6Accumulation of senescent cells Expression of p16INK4a Systemic SASP	6NF‐κB pathway activation Altered C/EBP family expression JAK/STAT pathway involvement Pro‐inflammatory cytokine release	5Suppression of preadipocyte differentiation Chronic inflammation Metabolic dysfunction
	Fat Distribution Changes	9↓ lower body SAT ↑ abdominal and VAT ↑ Perivascular adipose tissue Sexual dimorphism in fat accumulation	10Age‐related decline in sex steroid levels (oestrogen, testosterone), altering depot‐specific adipose regulation Age‐related emergence of regulatory cells SIRT family regulation (SIRT1, SIRT6, SIRT7)	8↑ chronic disease risk ↑metabolic disturbances (e.g., T2DM, CVD)
	Molecular pathway dysregulation	13Altered C/EBP family expression ↓ C/EBPα ↑ C/EBPβ‐LIP Impaired mitochondrial function	13CUGBP1 upregulation PPARγ suppression Oxidative stress mechanisms Reduced NAD+ levels	10Impaired adipocyte differentiation Compromised metabolic function Insulin resistance
Species differences	Translational considerations	17Consistent age‐dependent adipogenic decrease in mice More complex responses in human adipose tissue Vastly different lifespans	17Variations in cis‐regulatory elements Differences in ADSC behaviour Differences in genomic maintenance	13Limited applicability of animal models Caution when translating findings to humans

1.8. Systemic Consequences

Convergent NF‐κB activation, IL‐6/STAT3 signalling and TNF‐α‐mediated PPARγ suppression deepen peripheral and hepatic insulin resistance [28]. Ectopic lipid deposition at hepatic, myocellular and perivascular sites drives organ‐specific insulin resistance and lipotoxic injury through distinct but overlapping pathways: hepatic steatosis promotes de novo lipogenesis and impairs glucose output, myocellular lipid intermediates disrupt insulin receptor substrate signalling and perivascular accumulation sustains adventitial inflammation. The downstream clinical sequelae (Type 2 diabetes, atherosclerotic cardiovascular disease and sarcopenic frailty) reflect the aggregate lipotoxic burden across these compartments rather than failure at any single site. In preclinical adipose senescence models, JAK/STAT inhibition attenuates frailty indices and restores key metabolic endpoints, identifying senescence‐driven cytokine signalling as a druggable target upstream of systemic decline (Figure 3). Adipose inflammation can therefore be targeted to slow systemic ageing.

FIGURE 3.

Mechanisms of ageing‐associated dysregulation of adipose tissue. Age‐related adipose decline diverges from normal adipocyte maturation at several molecular nodes. Healthy adipogenesis occurs through a sequential cascade involving C/EBPβ/δ, PARP‐1 PARylation, followed by strong activation of PPARγ and C/EBPα, but age‐dependent dysregulation disrupts adipose homeostasis. Mitochondrial hyperfunction and protein aggregation result from ageing‐related chronic inflammation, DNA damage, oxidative stress, telomere attrition and cellular stress. Excess ROS then stimulates the NF‐κB signalling pathway. NF‐κB drives TNFα expression and activates the IL‐6/STAT3 pathway, which upregulates C/EBPβ‐LIP and CHOP, blocking adipogenesis. Senescent cells then accumulate and sustain chronic inflammation through SASP‐driven NF‐κB reactivation. Activin A secretion amplifies this state as a paracrine inhibitor of adipogenesis. Systemic metabolic dysfunction follows, linking adipose ageing to metabolic disease.

2. Transcriptional Reprogramming: C/EBP and PPARγ

Adipogenic commitment depends on three CCAAT/enhancer‐binding protein (C/EBP) isoforms: C/EBPβ initiates the cascade, C/EBPδ amplifies the early transcriptional response and C/EBPα drives terminal differentiation [29, 30]. Their activity is set across four regulatory tiers (gene induction, alternative translation initiation, heterodimerisation and post‐translational modification), which together shape DNA‐binding specificity and target‐gene selection at individual promoters [31]. At those promoters, C/EBPβ is reversibly poly(ADP‐ribosyl)ated by poly(ADP‐ribose) polymerase‐1 (PARP‐1), an event that modulates its transcriptional output without altering protein abundance or mRNA stability 32. Chromatin immunoprecipitation reveals C/EBPα‐PPARγ co‐occupancy at thousands of adipocyte‐specific enhancers, where the two factors reinforce each other's expression and lock committed preadipocytes into a feed‐forward terminal‐differentiation circuit [32].

This cascade is disrupted with ageing. Expression of C/EBPα and PPARγ declines while the inhibitory C/EBPβ‐LIP isoform rises, largely through CUGBP1‐mediated regulation [33]; inflammatory TNF‐α and C/EBP homologous protein (CHOP) signalling, combined with these changes, suppresses adipogenesis and favours hypertrophy over hyperplasia [34]. Progenitor differentiation is further inhibited by secreted activin A, a transforming growth factor‐β (TGF‐β)‐family factor, from accumulating senescent cells [35]. Lipid‐buffering capacity deteriorates as C/EBP signalling fails, triglyceride accumulates ectopically in hepatocytes and myocytes, and peripheral insulin resistance and cardiometabolic disease follow (Figure 3).

3. Sirtuin‐NAD ⁺ Dysregulation

3.1. Sirtuins as NAD ⁺‐Dependent Metabolic Sensors

The seven mammalian sirtuins catalyse NAD⁺‐dependent deacetylation, each with distinct substrate specificity: SIRT1, SIRT6 and SIRT7 are nuclear, SIRT2 is cytoplasmic, and SIRT3–SIRT5 reside in the mitochondrial matrix [36]. Because catalysis depends on NAD⁺, sirtuin flux is constrained by three independent inputs: dietary status, mitochondrial redox balance and transcriptional load. Overfeeding depletes the NAD⁺ pool, whereas caloric restriction replenishes it and reactivates sirtuin‐dependent deacetylation; electron transport and active transcription consume NAD⁺ independently of diet [37]. NAD⁺ thus couples caloric intake to adipose remodelling and to the pace of biological ageing across organ systems.

3.2. SIRT1 in Adipogenesis, Lipid Metabolism and Inflammation

Within the PPARγ ligand‐binding domain, SIRT1 deacetylates lysine residues, suppressing transactivation and slowing differentiation. It also deacetylates PPARγ coactivator‐1α (PGC‐1α), raising mitochondrial oxidative capacity and insulin receptor substrate‐2 (IRS‐2), improving glucose disposal [38]. In adipose‐tissue macrophages, SIRT1 deacetylation of NF‐κB p65 and c‐Jun N‐terminal kinase (JNK) lowers pro‐inflammatory cytokine output and limits crown‐like‐structure formation. These actions are context‐dependent: on a high‐fat diet, adipocyte‐selective SIRT1 deletion improves systemic metabolism, with lower fasting glucose and greater hepatic insulin sensitivity than in wild‐type controls, because a deacetylase active in adipose, liver and muscle cannot be characterised by single‐tissue knockout alone [39].

3.3. SIRT2, SIRT3 and SIRT6

SIRT2 deacetylates FOXO1 to shift its nuclear‐cytoplasmic partitioning, modulating adipogenesis and peripheral insulin sensitivity [40]. In the mitochondrial matrix, SIRT3 deacetylates electron‐transport‐chain subunits to sustain respiration, fatty‐acid β‐oxidation and brown‐adipose thermogenesis [41]. SIRT6 acts in opposing directions at different stages of adipogenesis: its activity is required for early clonal expansion, whereas at later stages SIRT6‐catalysed FOXO1 deacetylation suppresses terminal maturation [42]. Through H3K9 and H3K56 deacetylation, SIRT6 also couples sirtuin activity to heterochromatin maintenance, connecting enzymatic decline with the epigenetic drift of ageing [43].

3.4. SIRT7 as a Regulator of Adipocyte Differentiation

SIRT7 drives adipocyte differentiation through a dual mechanism: inhibiting SIRT1 while enhancing PPARγ‐driven transcription at adipocyte‐specific promoters [44]. SIRT7‐knockout mice show reduced white adipose mass across depots and impaired ex vivo adipogenesis from stromal‐vascular progenitors, yet paradoxically improve glucose tolerance under high‐fat feeding despite reduced adipose expandability [44, 45]. Tissue compartment and dietary context therefore determine whether SIRT7 gain or loss favours metabolic health (Table 2). Across the seven‐member family, isoform‐specific and tissue‐restricted functions (varying by depot, diet and developmental stage) erode adipose plasticity as sirtuin regulation fails and complicate the identification of single therapeutic targets.

TABLE 2.

Effects of SIRT7 manipulation on adipogenesis and metabolic regulation. Data from knockout and overexpression models. Loss of SIRT7 reduces white adipose mass and impairs adipogenesis but can improve glucose tolerance and protect against high‐fat‐diet‐induced obesity. SIRT7 overexpression instead enhances adipogenic differentiation through PPARγ activation. SIRT7 exerts context‐dependent effects on adipose ageing.

Knockout model	Lifespan	Insulin sensitivity	Glucose levels	Key characteristics	References
Cardiac‐specific SIRT7 knockout mice	↓	—	—	Heart with extensive fibrosis Heart hypertrophy Inflammatory cardiomyopathy Diminished resistance to oxidative and genotoxic stress ↑ Basal apoptosis ↓ Cardiac function ↑ Inflammatory markers	[46]
Liver‐specific SIRT7 knockout mice	—	—	—	Multisystemic mitochondrial dysfunction Cardiac dysfunction Hepatic microvesicular steatosis Age‐related hearing loss ↑ Blood lactate ↓ Exercise performance ↓ Mitochondrial content ↓ ATP production ↑ Oxidative stress	[47]
Whole‐body SIRT7 knockout mice on high‐fat diet	—	↑ (HFD)	↓(HFD)	↓ Accumulation of hepatic lipid droplets‐ HFD ↓ Hepatic triglyceride‐ HFD ↓ Liver weight‐ HFD ↓ Obesity ‐HFD ↓ Epididymal WAT ↓ CD36 – HFD ↓ Serum leptin—HFD ↓ Body weight gain ↑ β‐oxidation ↓ Lipogenesis	[48]
Whole‐body SIRT7 knockout mice	↓	—	—	Partial embryonic lethality Progeroid‐like phenotype ↑ Replication stress Impaired DNA repair ↓ Genomic stability ↑ DNA damage response	[49]
Whole‐body SIRT7 knockout mice	—	—	—	↓ Adipocyte differentiation ↓ White adipose tissue ↑ SIRT1 activity ↓ PPARγ ↓ Fat mass ↑ Energy expenditure ↓ Food intake	[44]
Osteoblast‐specific SIRT7 knockout mice	—	—	—	↑↑ osteopenia ↓ Bone formation ↑ Osteoclasts ↓ Bone mineral density ↓ Bone volume ↓ Osteoblast differentiation	[50]
Whole‐body SIRT7 knockout mice (C57BL/6 background)	↑ (Male)	↑	↓	↑ FGF21 ↑ ATF4 mRNA ↓ Body weight ↑ Physical activity ↑ Energy expenditure ↑ Oxygen consumption	[45]

4. Nuclear Lamina and LMNA/C

4.1. Nuclear Lamins: Structure and Function

Nuclear lamins are Type V intermediate filaments that polymerise into a meshwork beneath the inner nuclear membrane, preserving envelope integrity and organising chromatin [51]. A‐type lamin expression is developmentally regulated, and lamina–chromatin coupling sets the epigenetic state and transcriptional potential of the genome during differentiation [52]. Beyond mechanical support, lamins govern DNA replication, nuclear‐envelope anchoring and cellular plasticity [53].

4.2. LMNA/C Mutations and Lipodystrophic Syndromes

Mutations in LMNA/C (lamin A/C) cause laminopathies including muscular dystrophy, cardiomyopathy, conduction disease and partial lipodystrophy [54]. Alternative splicing of the LMNA/C transcript yields LMNAΔ10 and LMNAΔ50; the latter encodes progerin, whose accumulation at the nuclear lamina defines Hutchinson–Gilford progeria syndrome and disrupts nuclear architecture [55, 56]. Affected patients show accelerated senescence with insulin resistance and dyslipidemia, a consequence of lamin dysregulation [57].

4.3. LMNA/C Effects on Adipocyte Differentiation

Laminopathy alleles directly impair adipogenesis. The recurrent lipodystrophy substitution R482W reprograms adipogenic enhancers and upregulates the anti‐adipogenic microRNA MIR335, causing terminal differentiation to fail [58, 59]. Even wild‐type lamin A inhibits PPARγ2 transcriptional activity and downstream insulin signalling, and progerin blocks adipogenesis still more completely: cell‐culture and transgenic models expressing progerin uniformly fail to differentiate [60, 61]. Both wild‐type and mutant lamin A therefore suppress adipogenic transcriptional networks.

4.4. Molecular Mechanisms of LMNA/C in Adipogenic Regulation

Pathogenic lamin variants reorganise lamina‐associated domain boundaries and reduce chromatin accessibility at adipogenic loci, directly attenuating the binding of pioneer transcription factors, most prominently PPARγ and C/EBPα, to their target enhancers during the commitment window. The PPARγ E3 ubiquitin ligase MKRN1 mediates progerin's suppression of PPARγ‐driven transcription, arresting differentiation at the commitment stage [62]. Lamina‐associated domains reorganise dynamically during adipogenesis, providing a spatial framework for lineage‐specific gene activation [63], while H2B GlcNAcylation at lamin‐tethered domains couples nutrient availability to chromatin accessibility at adipogenic loci [64]. Because lamin expression and lamina organisation change with age, adipogenic regulatory regions may progressively lose accessibility, a mechanistic link between impaired adipogenesis and age‐related metabolic decline [65].

5. Cellular Senescence and the SASP

5.1. Replicative Senescence in Adipose Progenitors

Under replicative senescence, adipose‐derived progenitors accumulate senescence markers, lose adipogenic capacity and hypertrophy [66]. Specific triacylglycerol species accumulate on lipidomic profiling, consistent with lipotoxic stress driving adaptive remodelling of the lipidome, and diverse lipid classes help initiate and maintain the senescent state while limiting differentiation potential [67, 68].

5.2. Regulatory Pathways in Adipose Senescence

Several pathways converge on this loss of competence. p53 upregulation, obesity‐driven, constrains oxidative stress while suppressing adipogenesis, promotes senescence and amplifies adipose inflammation [69, 70]; INK4a/ARF locus products act as a metabolic switch in obesity pathogenesis [71]. p53 and p16INK4a rise as senescent cells accumulate, and activin A and cytokines, SASP‐derived, disrupt the differentiation of neighbouring progenitors, establishing a microenvironment that suppresses adipogenesis [35, 72]. Notch, Wnt and Sonic Hedgehog signalling become dysregulated with age while caveolin‐1 rises [73], and lipopolysaccharide exposure accelerates premature senescent conversion, further reducing adipogenic capacity [74].

5.3. Stress‐Induced Premature Senescence

Sublethal stress stimuli induce an irreversible growth arrest. SIPS (stress‐induced premature senescence) differs from replicative arrest in that telomere attrition is not required [75]. The SIPS proteome is remodelled at the level of energy metabolism, antioxidant defence, signal transduction and redox maintenance [75]. Upstream genotoxic and oxidative stimuli signal through p53 to upregulate p21, with p16INK4a providing a parallel enforcement arm for sustained growth arrest [76]. As SIPS cells accumulate over time, they secrete pro‐inflammatory mediators that erode insulin sensitivity and metabolic function in adipose tissue over time.

6. Therapeutic Strategies

6.1. The Therapeutic Paradox

Preadipocyte commitment declines with age while triglyceride storage capacity is maintained or expanded [25]. Both defects require concurrent correction. PPARγ‐responsive promoters lose C/EBPα and C/EBPβ occupancy [25], and p16INK4a with p21 lock preadipocytes and mature adipocytes into irreversible growth arrest [77]. IL‐6, TNF‐α and MCP‐1 (released through NF‐κB → NLRP3 activation in the stromal‐vascular fraction) feedback on neighbouring cells, worsening the transcriptional and senescent deficits via paracrine loops [28]. Restoration of C/EBP‐PPARγ transcriptional co‐occupancy at adipogenic enhancers and selective clearance of senescent stromal cells address mechanistically distinct lesions and are therefore non‐redundant therapeutic requirements; resolution of the sterile NF‐κB–NLRP3 inflammatory axis within the stromal‐vascular fraction is a third, equally essential target, because paracrine cytokine flux from senescent and activated immune cells will otherwise continuously suppress any restored differentiation programme (Table 3).

TABLE 3.

Mechanisms linking adipose ageing to weight gain. Ageing adipose tissue exhibits downregulation of adipogenic transcription factors (C/EBPα, PPARγ) together with SASP‐driven inflammation, NF‐κB activation and stress signalling (CHOP; JAK/STAT). Repression of SIRT1/6/7 and perturbations in LMNA/C further impair differentiation and reinforce senescence. These defects, together with systemic shifts (slower lipid turnover, reduced basal metabolic rate and diminished BAT thermogenesis), produce blunted adipogenesis together with enhanced fat storage [9, 33, 44].

Mechanisms	Inhibition of adipogenesis	Weight gain with ageing
Adipocyte dynamics	Reduced C/EBPα and PPARγ expression impair new adipocyte formation.	Hypertrophy of existing adipocytes compensates, leading to increased lipid storage.
Inflammation	SASP cytokines (IL‐6, IL‐1β, TNF‐α) activate NF‐κB, inhibiting adipogenesis.	Chronic inflammation promotes lipid storage, reduces lipid turnover and alters adipokine secretion.
Cellular senescence	Senescent preadipocytes secrete SASP, impairing differentiation via paracrine effects and CHOP activation.	Senescent adipocytes exacerbate systemic inflammation, disrupting energy homeostasis.
SIRTs	Reduced SIRT1 inhibits PPARγ and C/EBPα, suppressing differentiation.	SIRTs dysregulation promotes fibrosis and fat redistribution (e.g., SIRT7 inhibits SIRT1, which reduces SIRT1's anti‐fibrotic effects through decreased prevention of fibroblast activation and collagen deposition).
Lamins (LMNA/C)	Mutations (e.g., Progerin) impair PPARγ2 and C/EBPα, blocking adipogenesis.	Defective lamins disrupt nuclear integrity, accelerating senescence and fat redistribution to visceral depots.
Energy expenditure	Not directly related to adipogenesis.	Decline in BMR, reduced BAT activity and lower physical activity drive fat accumulation.
Hormonal changes	Decline in adipogenic signals (e.g., insulin sensitivity) reduces differentiation potential.	Decreased oestrogen and testosterone promote visceral fat accumulation.
Fat redistribution	Impaired adipogenesis contributes to reduced subcutaneous fat.	Increased visceral and ectopic fat deposition due to impaired lipid buffering.
Lipid turnover	Not a primary mechanism for adipogenesis inhibition.	Slower lipid turnover increases triglyceride storage, contributing to weight gain.
Insulin resistance	Suppresses preadipocyte differentiation through altered signalling.	Promotes lipid storage in adipocytes and ectopic depots.
Diet and lifestyle	Indirectly linked through metabolic alterations.	Overeating and reduced physical activity contribute to caloric surplus and fat gain.
Stress pathways	Activation of NF‐κB, CHOP and JAK/STAT suppresses differentiation.	Stress signalling enhances chronic inflammation and lipid storage.

6.2. Senolytic Clearance of Senescent Cells

Senolytic clearance of senescent cells has advanced furthest along the translational continuum, with dasatinib‐quercetin completing Phase I evaluation in diabetic kidney disease and idiopathic pulmonary fibrosis [78, 79], two pathologies mechanistically distinct from adipose ageing yet sharing the same senescent‐cell burden as a driver of tissue dysfunction. The molecular basis for selective senolytic activity resides in the aberrant upregulation of BCL‐2, BCL‐XL and BCL‐W in senescent cells, which navitoclax and ABT‐737 act by competitively displacing pro‐apoptotic BH3‐only proteins from these survival complexes, restoring the intrinsic apoptotic threshold that senescent cells have pathologically raised to resist elimination [80].

Senescent adipose cells carry excess BCL‐2/BCL‐XL prosurvival signalling that healthy BCL‐XL‐low neighbours lack [81]. Visceral fat clusters positive for p16INK4a and p21 secrete IL‐6, TNF‐α, MCP‐1 and PAI‐1 at inflammation‐sustaining rates [28, 77]. Recruited M1 macrophages then injure adjacent preadipocytes; glucose disposal and hepatic lipid handling deteriorate [28, 77].

p16INK4a‐high cell ablation in INK‐ATTAC mice improved metabolic function and extended median lifespan [12, 13, 82]. A screen of 46 candidates then identified dasatinib–quercetin (dasatinib inhibiting Src‐family and ephrin receptor kinases, quercetin acting on phosphoinositide 3‐kinase) as a broadly effective senolytic that lowers IL‐6 and MCP‐1 output from treated depots [83]. Navitoclax binds BCL‐2/BCL‐XL/BCL‐W with sub‐nanomolar affinity, but its metabolic response is diet‐dependent. Intermittent dosing in obese mice cleared senescence markers without the sustained thrombocytopenia of continuous exposure [84]. A1331852 and A1155463 may further reduce hematologic toxicity [85]. Fisetin cleared senescent cells across tissue compartments in aged mice [85]. Palmer, Xu et al. [13] confirmed improved glucose uptake via a BCL‐2‐independent mechanism. Insulin‐resistance severity in humans tracks adipose senescence‐marker load [86].

Three completed trials now provide proof‐of‐access to human adipose tissue [78, 79, 87]. Diabetic kidney disease patients received dasatinib plus quercetin for 3 days; adipose senescent‐cell frequency and macrophage infiltration dropped within 11 days [78]. Idiopathic pulmonary fibrosis was the second indication. Physical function improved [79]. Intermittent‐dosing tolerability was confirmed in a randomised placebo‐controlled pilot [87]. None of the three cohorts had adequate power for metabolic endpoints.

Although post‐treatment adipose biopsies confirmed pharmacologically active drug concentrations at the target site [87], critical parameters (dosing interval, treatment duration and agent sequencing) remain unresolved, compounded by the phenotypic heterogeneity of senescent cells across depot origin, progenitor lineage and inducing stimulus [84], which prevents a unified protocol and requires depot‐stratified trial design.

6.3. Cell‐Based Strategies

Lipoaspirate yields adipose‐derived stem cells (ADSCs) with multipotent differentiation capacity and a secretome rich in growth factors and immunomodulatory mediators [88]. Radiation injury and chronic wound models responded to ADSC‐based interventions [88]. ADSC proliferation declines with senescence and age [89]. Autologous transplantation remains viable. Thermogenic beige and brown adipocytes derived from induced pluripotent stem cells (iPSCs) engraft into vascularized depots in mice [90]. BMP7, rosiglitazone and staged PPARγ activation each raise iPSC‐to‐adipocyte yield above the baseline, lower than from adult stromal‐vascular progenitors [91]. Genetic tractability and isogenicity make iPSCs useful for modelling adipogenesis and screening interventions prior to in vivo testing [92].

6.4. Molecular Strategies

Cantó, Menzies et al. [93] and de Lange, Lombardi et al. [94] documented declining biosynthetic flux in aged white adipose tissue, with consequent mitochondrial redox imbalance and impaired sirtuin‐dependent deacetylation. Yoshino, Mills et al. [95] restored NAD⁺ pools in aged mice with nicotinamide mononucleotide (NMN), while nicotinamide riboside (NR) independently improved glucose tolerance [96]. Nicotinamide phosphoribosyltransferase (NAMPT)‐driven salvage rate‐limits adipose NAD+ repletion [97]. A parallel axis operates through metabolic‐sensing kinases. Metformin suppresses mitochondrial reactive oxygen species output through AMP‐activated protein kinase (AMPK) engagement in adipocytes and hepatocytes [98]. Brown‐adipocyte commitment followed AICAR and A‐769662 exposure, with concurrent CpG‐methylation shifts at UCP1 and PRDM16 [99, 100]. Glucose tolerance improved in parallel with both activators.

Pan‐HDAC inhibition with trichostatin A shifted adipogenic promoter occupancy, suppressed fibrotic programmes and elevated Thr172 AMPK phosphorylation in murine and human preadipocytes [101], while SIRT1‐mediated deacetylation of PGC‐1α and FOXO1 drove the parallel glucose‐disposal improvement [102]; SIRT3 extends this oxidative remodelling to the mitochondrial matrix through analogous deacetylation of SOD2 and IDH2 [103]. mTORC1, at the intersection of nutrient and growth‐factor signals governing progenitor self‐renewal and lipid storage [104], is a distinct node: adipose stem‐cell dysfunction in aged mice responded to rapamycin [105], with SASP attenuation confirmed independently in rapamycin‐treated depots [106]. Circulating IGF‐1 declines with age in parallel with adipogenic capacity and lipolytic responsiveness [107, 108], and attenuated depot‐level retention is insufficient to sustain downstream signalling [108].

6.5. Incretin‐Based Therapies: GLP‐1 and Dual GIP/GLP‐1 Receptor Agonists

Seventeen thousand six hundred and four patients entered SELECT; 2539 entered SURMOUNT‐1 [109, 110]. Both programmes established incretin agonists as first‐line obesity pharmacotherapy. GLP‐1R and GIP‐R activation exerts depot‐level metabolic effects independent of appetite suppression [111, 112], but weight loss, not direct depot action, drove the bulk of cardiometabolic benefit in SELECT and SURMOUNT‐1 [109, 110]. Semaglutide acts through hypothalamic GLP‐1R engagement to lower caloric intake and potentiate glucose‐dependent insulin secretion [109]. For fat loss in SURMOUNT‐1, tirzepatide, a dual GIP/GLP‐1 agonist, exceeded all GLP‐1‐selective comparators [110]. Visceral and ectopic depots contracted preferentially over subcutaneous stores. Portal free‐fatty‐acid flux fell. Liver, myocardial and islet triglyceride content fell with semaglutide and tirzepatide [109, 110]. Among SELECT participants, who had obesity without diabetes, semaglutide reduced major adverse cardiovascular events (MACE) [109]. Top‐dose tirzepatide in SURMOUNT‐1 produced 22.5% body‐weight loss [110].

Direct adipose actions of GLP‐1R agonism are plausible but unquantified in human depots [111, 112]. GLP‐1 receptor mRNA is detectable in human omental fat. GIP receptor protein is detectable in subcutaneous fat biopsies [111, 112]. Incretin exposure in adipose explants suppresses NF‐κB‐dependent IL‐6, TNF‐α and MCP‐1 transcription and concurrently shifts adipokine output, lipolytic flux and endoplasmic‐reticulum stress markers [111, 112]. C/EBP–PPARγ adipogenic programmes and incretin‐activated cascades share functional network membership on pathway‐enrichment analysis [111]. Receptor density on mature human adipocytes has not been quantified. Vagal, hepatic and immune intermediaries may mediate much of the apparent depot‐level effect. Paired clamp studies, with and without caloric restriction, would be needed to separate weight‐loss‐independent remodelling from the dominant weight‐loss‐driven component; none have been performed. SELECT and SURMOUNT‐1 together make incretins the most clinically validated means of reducing systemic and depot‐level adipose burden [109, 110]. A near‐term combinatorial approach pairs an incretin backbone with dasatinib–quercetin, NMN/NR or AMPK activators.

6.6. Adipose Tissue Engineering

Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 editing has resolved causal mechanisms at multiple adipose loci, including FTO/IRX3/IRX5 and UCP1 [113, 114]. In human preadipocytes, Kamble and colleagues [113] edited FTO/IRX3/IRX5 to define regulatory control over terminal differentiation. Thermogenic CRISPR editing induced UCP1 expression in white adipocytes, improving glucose homeostasis and reducing diet‐induced fat expansion [115]. Aged adipose mesenchymal stem cells regained clonogenic capacity after CRISPRa‐mediated reactivation of the SIRT1 promoter [114], and NRIP1 disruption raised UCP1‐driven thermogenesis, with fasting glucose, triglycerides, and insulin normalising in parallel. No CRISPR‐based strategy has yet entered a human adipose‐ageing trial [113, 114].

6.7. Integrative Approaches

Senescence within ageing depots acts on multiple cell types simultaneously (adipocytes, preadipocytes, endothelium and resident macrophages), so no single‐target intervention can restore depot function. Dasatinib–quercetin clears senescent visceral cells [78, 83]; caloric restriction and aerobic exercise lower IL‐6 release and crown‐like‐structure density in visceral fat; and NMN, NR and AMPK agonists restore mitochondrial oxidative capacity through deacetylation and phosphorylation pathways [116, 117]. Because visceral, subcutaneous, perivascular and bone‐marrow depots age along divergent trajectories [118], intervention must be matched to the dominant mechanism within each depot and patient phenotype (Table 4).

TABLE 4.

Therapeutic strategies targeting adipogenic dysfunction. Interventions targeting ageing‐associated adipose decline. Strategies include senolytics to clear senescent cells, stem‐cell‐based therapies, NAD⁺ boosters, AMPK activators, epigenetic modulators, anti‐inflammatory approaches, metabolic reprogramming agents, mTOR inhibitors and hormone therapies. Novel tools such as CRISPR gene editing, along with nutraceutical and lifestyle interventions, add precision. Combinatorial strategies target adipogenic capacity, mitochondrial function and lipid homeostasis [1, 13, 96, 101, 118].

Categories	Therapeutic approach	Mechanism of actions	Potential benefits	Examples
Existing therapeutic approaches	Senolytic drugs	Clear senescent cells via BCL‐2/BCL‐XL inhibition Unblock progenitor differentiation and lipid buffering	Better glucose tolerance and insulin sensitivity Metabolic improvement	Dasatinib and Quercetin combination, Unity Biotechnology's UBX0101, Navitoclax (ABT‐263)
Cellular and molecular interventions	Stem cell therapies	3Supply fresh progenitors from lipoaspirate or iPSC sources 4Replenish adipose progenitor pools	3Recovered progenitor differentiation 4Metabolic recovery	ADSCs, iPSC‐derived adipogenic progenitors, Autologous adipose‐derived stem cell transplantation
	NAD+ boosters	5Replenish cellular NAD+ levels 6Boost mitochondrial NAD+ and oxidative flux	5Better mitochondrial and metabolic output	NMN (Nicotinamide Mononucleotide) and NR (Nicotinamide Riboside)
	AMPK activators	7Activate AMPK‐dependent metabolic programmes 8Stimulate mitochondrial biogenesis	6Better insulin sensitivity and energy expenditure	Metformin, AICAR, A‐769662
	Epigenetic modulators	9Reverse age‐associated histone modifications 10Re‐open silenced adipogenic promoters	7Restored adipogenic gene expression	HDAC inhibitors (e.g., trichostatin A)
	Targeted anti‐inflammatory interventions	11Attenuate NF‐κB‐driven depot inflammation 12Use of pro‐resolving mediators (SPMs)	8Lower inflammation 9Improved depot homeostasis	Resolvins, Protectins, Maresins
	Metabolic reprogramming agents	13Reactivate sirtuin‐dependent oxidative pathways 14Act through sirtuin deacetylation and UCP1 uncoupling	10Higher energy expenditure 11Improved adipocyte function	SIRT1/SIRT3 activators, mitochondrial uncoupling agents
	mTOR inhibitors	15Suppress mTORC1‐driven senescence and SASP 16Shift autophagy‐to‐growth balance toward clearance	12Metabolic benefit	Rapamycin
	Hormone and growth factor therapies	17Supplement declining IGF‐1 and sex‐steroid signalling	13Restored adipogenic capacity 14Depot renewal	IGF‐1, adipogenic growth factors [119]
Emerging technological approaches	CRISPR/Gene Editing	18Edit specific adipogenic or lipid‐metabolism lociat adipogenic and lipid‐metabolism loci	15Corrected gene expression at target loci 16Better depot function	CRISPR‐mediated SIRT1 activation, PPARγ locus editing, CRISPR knockout of senescence‐associated genes like p16INK4a
Lifestyle and nutraceutical interventions	Targeted nutritional supplements	19Provide anti‐inflammatory and lipid‐modulating substrates	17Lower depot inflammation 18Better lipid turnover	Omega‐3 fatty acids, polyphenols, micronutrients
Integrated therapeutic approaches	Combinatorial strategies	20Combine agents matched to individual depot pathology	19Lower senescent‐cell load 20Restored adipogenic and oxidative capacity 21Normalised lipid flux	Combining senolytic drugs with NAD+ boosters, AMPK activation paired with epigenetic modulation, SIRT1 activators with metformin and nutritional supplements

6.8. Translational Readiness and Barriers

Translational readiness varies: some strategies have completed Phase I–II trials while others remain preclinical [78, 87]. Senolytics and incretins lead, both having entered controlled human testing [79, 87, 109, 110]. NMN and NR have completed early‐phase safety evaluation but lack adipose‐specific efficacy data. Metformin and rapamycin analogues reached preclinical proof of concept [98, 105]; HDAC and sirtuin modulators lack trials with depot‐specific endpoints. ADSC, iPSC, CRISPR and growth‐factor approaches remain preclinical [113, 114].

Specificity remains a primary barrier. Senescent cells vary phenotypically across depots, lineages and stimuli, with no universal surface antigen permitting selective targeting [84]. BCL‐XL‐directed agents carry on‐target thrombocytopenia that limits navitoclax dose escalation. Delivery is a parallel barrier: systemically distributed agents cannot yet achieve the depot selectivity required. Sparing subcutaneous fat while clearing inflamed visceral senescent cells demands precision that current delivery platforms cannot meet. Adipose‐homing peptides, lipid nanoparticles and progenitor‐selective vehicles remain at proof of concept.

Senolytics and incretins now meet the criteria for depot‐ and biomarker‐guided efficacy trials [78, 87]. NAD+ repletion and metformin repurposing are positioned for adipose‐focused Phase II studies with biopsy endpoints. Three questions cut across all strata. Lineage tracing in human biopsies, not inference from surrogate markers, is the only way to determine whether senescent‐cell clearance actually restores progenitor competence or merely unloads stored lipid. Which intervention suits which depot and phenotype requires stratification biomarkers that do not yet exist. Whether minimally invasive circulating or imaging markers can guide therapy initiation and duration also remains open, none validated to date.

7. Conclusion and Future Directions

Adipogenic commitment wanes with age across all four depot classes: subcutaneous, visceral, perivascular and bone‐marrow [25]. Triglyceride accumulation, by contrast, persists or even expands. Systemic metabolic homeostasis deteriorates. C/EBPα, C/EBPβ and PPARγ transcriptional coordination declines in aged preadipocytes [25]. p16INK4a and p21 enforce senescent arrest [77]. SIRT1 through SIRT7 lose activity. Chromatin at adipogenic loci closes as the nuclear lamina remodels (Section 4). Stromal‐vascular NF‐κB and NLRP3 cascades intensify. TNF‐α, MCP‐1, PAI‐1 and IL‐6 output climbs, worsening macrophage infiltration and paracrine preadipocyte injury [28, 77]. Type 2 diabetes, cardiovascular disease, and established insulin resistance emerge downstream through the adipose–hepatic–systemic inflammatory axis [28, 77].

Therapeutic intervention can now target six distinct mechanistic nodes [83, 114]. Dasatinib–quercetin, navitoclax and ABT‐737 ablate senescent adipose cells. BCL‐XL‐low healthy counterparts survive [83]. Intermittent navitoclax dosing spares platelets while retaining senolytic efficacy [84]. CRISPRa‐mediated SIRT1 promoter activation rescued aged mesenchymal stem cells [114]. Three gaps remain open: whether senescence causes or merely accompanies metabolic decline, how depot‐specific trajectories should be matched to therapy, and which biomarkers could stratify patients, none yet defined. Until these gaps close, the molecular targets mapped in Sections 2, 6 define where mechanism‐to‐bedside translation must focus and where biomarker development is most urgently needed.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Matar D. B., Elahi M. A., Nassar W. K., et al., “The Ageing Adipose Paradox: Implications for Metabolic Health,” Diabetes, Obesity and Metabolism 28, no. 9 (2026): 7752–7767, 10.1111/dom.71037.

Data Availability Statement

Data sharing is not applicable to this article, as no new data were created or analysed in this study. All data discussed are available in the cited published literature.