https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70519
I find this interesting because it rides on my hobbyhorse. OTOH I think the target is acetylation (more) rather than deacetylation (less)
chatGPT:
Summary
This paper argues that HDAC9 promotes age-related adipose-tissue dysfunction, and that deleting the Hdac9 gene in mice reduces adipose senescence, improves mitochondrial function, and preserves a metabolically healthier fat phenotype. The core claim is that rising HDAC9 in aging adipose tissue helps drive senescence and mitochondrial impairment, partly through suppression of TST / thiosulfate sulfurtransferase, a mitochondrial sulfur-transfer enzyme.
The authors first show that Hdac9 expression rises with age in mouse visceral and subcutaneous fat, alongside senescence markers such as Cdkn1a/p21 and Cdkn2a/p16. They then compare wild-type mice with global Hdac9 knockout mice. The knockout mice gain less weight during aging, have less fat mass, smaller visceral and subcutaneous fat depots, lower fasting glucose, and a trend toward improved insulin sensitivity.
A major experimental finding is that adipose tissue from Hdac9 knockout mice shows less senescence-associated β-galactosidase staining and lower expression of senescence/SASP markers. Isolated preadipocytes from knockout mice are also less prone to baseline and stress-induced senescence after hydrogen peroxide or UV exposure, suggesting that the effect is not only indirect through whole-body leanness but may be partly cell-autonomous in preadipocytes.
RNA-seq of visceral fat shows broad transcriptional changes after Hdac9 deletion: adipogenesis and fatty-acid metabolism pathways are upregulated, while inflammatory pathways, p53-related pathways, senescence markers, and SASP genes are reduced. The authors interpret this as evidence that HDAC9 may act as a broad regulator of adipose aging programs.
The mitochondrial part is important. Hdac9 knockout adipose tissue shows higher mitochondrial DNA content and higher oxygen-consumption parameters in Seahorse assays, including basal respiration, proton leak, and in some depots maximal respiration or non-mitochondrial oxygen consumption. The authors therefore link lower HDAC9 to greater adipose mitochondrial activity.
Mechanistically, the paper focuses on TST. TST is reduced in aged adipose tissue, restored or increased in Hdac9 knockout tissue, and increased in knockout-derived preadipocytes. Knocking down Tst in preadipocytes increases p16, p21, p53, and β-galactosidase staining. ChIP data suggest increased H3K9 acetylation at the Tst promoter in Hdac9 knockout preadipocytes, supporting the idea that HDAC9 normally represses Tst transcription.
The conclusion is that elevated HDAC9 is detrimental in aging adipose tissue, and that lowering HDAC9 may reduce adipose senescence and improve mitochondrial/metabolic function. The authors propose HDAC9 as a potential therapeutic target for healthier adipose aging.
What is novel?
The main novelty is the connection between HDAC9 and adipose aging, rather than only obesity or adipogenesis. Previous work had linked HDAC9 to adipocyte differentiation and diet-induced obesity, but this paper extends the role to age-related adipose senescence and mitochondrial dysfunction.
A second novel element is the proposed HDAC9–TST axis. The paper suggests that HDAC9 represses Tst, and that restoring TST may be one route by which Hdac9 deletion protects preadipocytes and adipose tissue from senescence. That is a mechanistically interesting bridge between chromatin regulation, sulfur metabolism, mitochondrial function, and senescence.
A third novel point is the tissue-specific contrast: the discussion notes that HDAC9 was previously reported as downregulated in aged brain and relevant to cognitive decline, whereas here it is upregulated in aged adipose tissue. That implies HDAC9’s role in aging may be strongly tissue-dependent.
The study also adds to a wider theme: senescence in preadipocytes may be a central contributor to age-related fat dysfunction, impaired adipogenesis, inflammation, ectopic lipid deposition, and metabolic decline.
Critique
The paper is strong in combining several levels of evidence: whole-animal phenotype, adipose-tissue staining, isolated preadipocyte stress experiments, RNA-seq, mitochondrial respiration assays, TST knockdown, and ChIP at the Tst promoter. The story is coherent: aging raises HDAC9; HDAC9 loss reduces adipose senescence; HDAC9 loss improves mitochondrial gene expression and respiration; TST is a plausible downstream mediator.
However, the main limitation is that the mouse model is a global Hdac9 knockout. This makes causality harder to assign specifically to adipose tissue or preadipocytes. The leaner phenotype itself could reduce adipose inflammation and senescence secondarily. The in vitro preadipocyte data help address this, but they do not fully exclude developmental or systemic effects of lifelong global Hdac9 deletion.
A second limitation is that many experiments use middle-aged rather than very old mice. Several assays are in 8–12-month or 10-month mice, whereas stronger claims about aging would be more convincing with 18–24-month cohorts. The authors themselves acknowledge that older-mouse metabolic phenotyping would strengthen the conclusions.
The TST mechanism is suggestive but not fully proven in vivo. Tst knockdown increases senescence markers in preadipocytes, but the paper does not show that TST is necessary for the anti-senescent effects of Hdac9 deletion in mice. A stronger test would be adipose- or preadipocyte-specific Tst knockdown/rescue in Hdac9 knockout animals.
The Seahorse adipose explant data are useful but inherently noisy. Adipose tissue is heterogeneous, and oxygen-consumption differences can reflect cell composition, adipocyte size, beige adipocyte abundance, vascular/stromal content, or mitochondrial density rather than purely intrinsic mitochondrial quality. The authors note that histological assessment of fibrosis and stromal composition would strengthen interpretation.
There is also a conceptual ambiguity around proton leak. Increased proton leak can indicate greater mitochondrial uncoupling and energy expenditure, which may fit the leanness phenotype, but it is not automatically “better mitochondrial function” in all contexts. It may be adaptive, wasteful, protective against ROS, or a sign of altered mitochondrial coupling depending on context.
The senescence readouts are plausible but not definitive. SABG, p16, p21, p53, and SASP markers are standard, but they can be influenced by stress, differentiation state, inflammation, and cell composition. More rigorous senescence characterization could include single-cell analysis, lineage tracing, senescence-specific transcriptomic signatures, DNA damage markers, and demonstration of irreversible growth arrest in relevant cell populations.
Bottom line
This is a credible and interesting paper. Its most important contribution is identifying HDAC9 as a candidate driver of adipose-tissue aging, linking it to preadipocyte senescence, mitochondrial dysfunction, inflammatory/SASP signalling, and reduced TST expression.
The claim that HDAC9 is a therapeutic target is plausible but still early. The strongest conclusion is not yet “HDAC9 inhibition will treat adipose aging,” but rather: HDAC9 rises in aging fat, and lifelong loss of HDAC9 in mice produces a leaner, less senescent, more mitochondrially active adipose phenotype, with TST as a promising downstream mediator.