Sirtuin Decline Drives Skin Aging Hallmarks

A comprehensive review published in Aging Cell synthesizes published evidence linking the cellular activities of sirtuins to the thirteen canonical hallmarks of skin aging. The study identifies sirtuins as a family of evolutionarily conserved enzymes that are integral to maintaining cellular homeostasis, particularly in response to ultraviolet radiation (UVR). By examining the roles of SIRT1 through SIRT7, the review highlights how the age-related decline in these enzymes contributes to the progressive breakdown of cellular repair mechanisms and the visible manifestations of aging, such as wrinkles, sagging skin, and aberrant pigmentation.

Sirtuins were first discovered in Saccharomyces cerevisiae and are characterized by their primary enzymatic activity: nicotinamide adenine dinucleotide (NAD+)-dependent deacetylation. In mammals, seven distinct sirtuin enzymes have been identified, each with specific subcellular locations and functions. SIRT1 and SIRT6 are primarily nuclear, where they maintain genomic stability through DNA repair and telomere protection. SIRT2 resides in the cytoplasm under basal conditions but translocates to the nucleus to regulate the cell cycle. The mitochondrial sirtuins, SIRT3, SIRT4, and SIRT5, regulate metabolism, ATP production, and energy stores in response to nutrient availability, while SIRT7 is uniquely located in the nucleolus, regulating ribosome biogenesis and the nucleolar stress response.

The review details how sirtuin functions specific to skin include maintaining the barrier and extracellular matrix (ECM) integrity, regulating keratinocyte differentiation, and facilitating repair. Undifferentiated keratinocyte stem cells in the basal layer of the epidermis rely on sirtuins for proper proliferation and differentiation. For instance, overexpression of SIRT1 or SIRT2 increases keratinocyte differentiation while reducing proliferation, whereas SIRT3 activity decreases mitochondrial reactive oxygen species (mtROS), thereby suppressing differentiation. SIRT2 also directly contributes to the paracellular barrier function by deacetylating the tight junction protein claudin-4, which is critical for maintaining the skin’s protective properties.

Within the dermal layer, sirtuins play a crucial role in preventing the breakdown of collagen and maintaining fibroblast structure. SIRT1 and SIRT6 prevent collagen degradation, while SIRT2 deacetylates α-tubulin to maintain cytoskeletal organization in fibroblasts. Cutaneous wound repair involves several stages, including inflammation, proliferation, migration, maturation, and remodeling. SIRT1 downregulates inflammatory mediators such as NF-κB, IL-6, and TNF-α, while activating fibroblast migration to the site of injury. Conversely, decreased SIRT3 expression, observed in the skin of diabetic patients, appears to result in a decline in skin fibroblast migration, highlighting the enzyme’s importance in tissue repair.

Ultraviolet radiation significantly impacts sirtuin expression and activity, with both UVA and UVB increasing reactive oxygen species (ROS) and inducing DNA damage. The majority of sirtuins are initially downregulated upon UV exposure, followed by complex, sirtuin-specific adaptive responses. In human skin biopsies, SIRT1 mRNA and protein levels decreased dose-dependently in middle-aged female subjects compared with non-exposed subjects, an effect driven by ROS-mediated JNK signaling. However, SIRT1 acts as a negative regulator of JNK signaling and UV-induced p53 acetylation, thereby reducing apoptosis. SIRT3 and SIRT4 exhibit a temporal, inverse pattern of expression in human keratinocytes, where noncytotoxic UVB doses initially suppress both, but SIRT4 rebounds within hours due to UV-induced decreases in microRNA-15b, while SIRT3 levels remain low.

The decline of sirtuin expression and activity is a natural consequence of chronological age. In human dermal fibroblasts (HDFs), age-related decline of SIRT1 was seen after age 40 in healthy females, while SIRT2 declines with age in keratinocytes. SIRT4, SIRT6, and SIRT7 expression was lower in aged HDFs and skin biopsies from aged volunteers compared with children and younger adults. This age-related decline is further exacerbated by the reduction of NAD+, a substrate essential for sirtuin activity. Multiple studies have demonstrated that NAD+ levels decrease during aging in numerous mammalian tissues, including human skin, due to reduced synthesis, increased consumption by DNA repair enzymes, and enhanced degradation by NADase CD38.

Genomic instability is a primary hallmark of aging, defined as the accumulation of DNA damage and impaired DNA repair mechanisms. The nuclear sirtuins SIRT1, SIRT6, and SIRT7 function in double-strand break (DSB) and point mutation repair, while SIRT3 translocates from the mitochondria to the nucleus in response to DNA damage. In human skin fibroblasts, SIRT1 deacetylates Xeroderma pigmentosum group A, an essential factor in the nucleotide excision repair (NER) pathway. Downregulation of SIRT1 results in increased sensitivity to UVR and reduced cell viability. SIRT6 is activated by oxidative stress via JNK phosphorylation and deacetylates H3K56, which recruits the chromatin remodeler SNF2h to DSBs, making the chromatin more accessible to repair factors.

Telomere attrition is another critical hallmark, where telomeres naturally shorten with age, limiting cell division and leading to cellular senescence. Both SIRT1 and SIRT6 stabilize telomeres, with SIRT6’s role demonstrated in human skin. SIRT1 enhances telomerase transcription in mouse embryonic fibroblasts, while SIRT6 activates telomeres’ DNA repair mechanisms in response to oxidative damage in human fibroblasts. Depletion of SIRT1 leads to telomere shortening and increased DNA damage, whereas SIRT6 deficiency results in increased chromosomal fusions and premature senescence. In aging skin, the loss of SIRT1-supported maintenance of telomere integrity and SIRT6-supported DNA repair likely contributes to the reduced renewal capacity of keratinocytes, particularly in response to UVR.

Epigenetic alterations, including histone modification and chromatin remodeling, also contribute to skin aging. Sirtuins are classified as Class III histone deacetylase enzymes and carry out epigenetic modifications by deacetylating histones, resulting in chromatin condensation and transcriptional silencing. Age-related loss of SIRT4 and SIRT6 in skin cells is associated with senescence. SIRT4 directly impacts the epigenetic modulation of the ten-eleven translocation 2 (TET2) enzyme in keratinocytes, while SIRT6 binds to and represses the activity of long interspersed element 1 (L1) retrotransposon. In senescent HDFs, SIRT6’s association with L1 loci is reduced, resulting in increased L1 activity and genomic instability.

Mitochondrial dysfunction progresses with age due to the accumulation of mutations, loss of proteostasis, and increased ROS. Sirtuins are critical for mitochondrial biogenesis and function, with SIRT3, SIRT4, and SIRT5 regulating metabolic pathways to maintain ATP levels. SIRT3 and SIRT5 reduce ROS levels, enhancing mitochondrial stability, while SIRT4 inhibits glutamate metabolism and can increase ROS levels under nutrient-depleted conditions. In aging skin, mitochondrial dysfunction is partly caused by an imbalance between mitochondrial fusion and fission. Reduced activity of all sirtuins impacts mitochondrial function, leading to increased oxidative stress, altered metabolic processes, and increased inflammatory pathways, which collectively put cells on the path to senescence or apoptosis.

Extracellular matrix (ECM) changes are among the most visible hallmarks of skin aging, characterized by a decrease in collagens and a decline in elastic fiber remodeling. SIRT1 and SIRT6 inhibit collagen degradation by suppressing inflammation. In HDFs, reduced SIRT1 and SIRT6 elevate MMP-1, which hydrolyzes collagen and accelerates the degradation of ECM components. The impact of sirtuin decline due to age or photoaging contributes to the loss of collagen and elastin, manifesting as wrinkles and loss of plumpness. Furthermore, the loss of sirtuins results in the ECM containing an increased number of senescent cells and senescence-associated secretory phenotype (SASP) mediators, which further exacerbate tissue degradation.

Chronic age-related inflammation, or “inflammaging,” accelerates many of the hallmarks of aging in skin. Sirtuins play an integral role in regulating molecules central to inflammatory pathways, particularly the NF-κB pathway. SIRT1 deacetylates the RelA/p65 subunit of NF-κB, while SIRT6 deacetylates histone H3K9 in the promoter region of NF-κB target genes, suppressing inflammation. Age-associated NAD+ and SIRT3 decline impacts the transcription of NF-κB and FOXO family members, exacerbating inflammation susceptibility. In vitro knockdown of sirtuins elevates inflammatory activity, with suppression of SIRT1 and SIRT6 increasing MMP levels in HDFs, which can degrade the ECM. These findings suggest that reduced sirtuin activity exacerbates inflammatory pathways, contributing to the overall aging process in the skin.

The review concludes that sirtuins are integral to the homeostasis of skin, providing protection and healing from environmental insults and maintaining the pool of epidermal stem cells. The decline in sirtuin activity impacts the majority of hallmarks of aging in skin, either directly or due to the integrated nature of these processes.

Subject of Research: Role of Sirtuins in the Hallmarks of Skin Aging

Article Title: Role of Sirtuins in the Hallmarks of Skin Aging

Article References: Kala, R., Rella, A., Eagle, W., Goyarts, E., Cao, J., Deng, B., Dong, K., Schmit, C., Cappock, M., Corallo, K., & Trivero, J. (2026). Role of Sirtuins in the Hallmarks of Skin Aging. Aging Cell, 25(11), Article e70789. https://doi.org/10.1111/acel.70789

Image Credits: AI Generated

DOI: 10.1111/acel.70789

Keywords: Role, Sirtuins, Hallmarks, Skin, Aging, scientific research