Winter Leaves Traces in Our DNA

Each winter brings familiar shifts in temperature, daylight, and other environmental cues. Yet, the effects of this seasonal change extend beyond what we can observe. Research shows that winter leaves molecular traces in human cells that influence various physiological processes, including gene activity, immune function, and metabolism, patterns supported by large multi-tissue transcriptomic and biomarker datasets.3,5,2 These subtle seasonal adjustments may help explain periodic variations in infection risk, inflammation, and even mood during the colder months.

Circadian rhythm provides a direct molecular interface that links changes in the seasons to human biology. Light exposure acts as a primary environmental signal, synchronizing internal clocks through retinal photoreceptors and the hypothalamic suprachiasmatic nucleus (SCN). This coordination regulates downstream metabolic, hormonal, and immune rhythms across multiple tissues.1,2

Human cells have been found to exhibit seasonal changes in gene expression, as evidenced by a large-scale transcriptomic analysis that reveals many genes are differentially expressed depending on the season. In contrast, core ‘clock’ components such as ARNTL, PER1, PER3, and NR1D2 show the most marked day–night differences across tissues, with some tissues also exhibiting seasonal shifts.3

These patterns suggest that circadian signaling varies in amplitude and timing throughout the year, which may contribute to seasonal differences in cellular activity, physiology, and systemic responses. This reflects the broader impact of environmental change on humans and provides a useful framework for anticipating seasonal variation in biological data.3

Hormonal pathways represent another mechanism through which seasonal changes in light exposure influence human physiology. Analyses of dim-light melatonin onset (DLMO) across seasons indicate that when expressed in standard time, summer DLMO appears ~1 hour earlier than winter; however, in local clock time DLMO remains similar across seasons, consistent with alignment to local clock time/light exposure rather than “sun time”.4

These seasonal shifts in melatonin rhythm and light-induced behavior suggest that variations in day length, along with other associated external factors, may have a significant impact on daily physiological mechanisms, including sleep patterns and metabolism.4

Seasonal changes have also been observed in stress-axis activity and related immune-metabolic biomarkers, including cortisol. Evidence suggests that cortisol and other stress-related markers follow distinct seasonal cycles corresponding with fluctuations in metabolic and inflammatory pathways throughout the year. These shifts in cortisol rhythms may influence subsequent inflammatory and metabolic regulation, potentially affecting susceptibility to infections or autoimmune activity at particular periodic intervals.5

Such physiological changes are clinically evident in conditions influenced by seasonal variations in light exposure and circadian timing, such as Seasonal Affective Disorder (SAD). Individuals with this condition often exhibit high seasonality, reduced circadian amplitude, and a delayed circadian phase in winter, along with associations to clock-gene variants that can reproduce seasonal amplitude/phase phenotypes in models.6

Immune activity exhibits consistent seasonal variation, with increased expression of inflammation-related genes during the winter months. A shorter photoperiod, lower temperatures, and pathogen exposure interact with circadian and endocrine pathways, priming immune cells for heightened inflammatory and defensive responses.5,3

Winter months, commonly associated with higher rates of respiratory viral infections, coincide with enhanced basal inflammatory signaling. Seasonal fluctuations are also reported in autoimmune disease activity, with flare-ups in conditions such as rheumatoid arthritis (RA) and multiple sclerosis (MS) becoming more frequent during colder months, reflecting the systemic impact of winter on immune regulation.7,8

At the molecular level, genes involved in inflammatory cascades and interferon responses exhibit seasonal variation, suggesting fluctuations in immune activity throughout the year. For example, interferon-stimulated genes, which play key roles in antiviral defense, show higher expression in specific tissues during winter, reflecting coordinated shifts in immune-related pathways. Such periodic changes may influence vaccine responses, suggesting that timing can also be crucial for certain immunomodulatory interventions.3

During winter, cold exposure triggers adaptive metabolic responses that link seasonal conditions to underlying molecular processes, enabling the body to maintain energy balance and thermal homeostasis.9

When ambient temperatures decline, brown adipose tissue (BAT), specialized for thermogenesis via uncoupling protein-1 (UCP1), increases mitochondrial proton leak, generating heat at the expense of adenosine triphosphate (ATP) production. Simultaneously, sympathetic activation elevates norepinephrine release, which stimulates β3-adrenergic receptors in BAT, promoting lipolysis and initiating transcriptional programs that support thermogenic activity and mitochondrial biogenesis.9

Repeated cold exposure also induces longer-term BAT adaptations by enhancing oxidative capacity and reprogramming its metabolic profile, modifying the expression of genes involved in lipid metabolism, glucose usage, and endocrine signaling.9

Over time, this remodeling creates a seasonal metabolic signature, illustrating how sustained environmental cues can fine-tune energy homeostasis across multiple pathways.

Several model organisms demonstrate how daylight cues orchestrate seasonal adaptations that confer a survival advantage, with species-specific responses providing useful biological parallels for human physiology.

One example is the fruit fly, which adjusts its reproductive activity, diapause entry, and circadian timing in response to changing photoperiods, reflecting coordinated alterations in clock-gene expression and neuroendocrine signaling.10

In vertebrates, the Siberian hamster exhibits light-dependent changes in melatonin secretion during shorter winter days, which drive seasonal shifts in reproduction, body weight, and social behavior through melatonin-responsive neuroendocrine pathways.11 Similarly, the Japanese quail demonstrates photoperiod-controlled reproductive cycling via hypothalamic neurotransmitters and gonadal steroids, providing a model for neuroendocrine responses to seasonal light variation.12

The Arctic ground squirrel integrates photoperiodic cues with internal timing to regulate hibernation onset and arousal cycles, preparing for extreme drops in body temperature and metabolism.13 Whereas large mammals at extreme latitudes, such as reindeer, display dampened or absent daily rhythms during continuous summer light or polar night, yet maintain robust seasonal responses even when circadian cues are weak.14

Exploring how recurring winter seasonal trends influence human cells enhances our understanding of the interplay between the environment and systems biology, providing a foundation for incorporating seasonality into healthcare.

Emerging approaches in circadian and seasonal medicine, such as chronomedicine, treat temporal information as a measurable and clinically relevant variable. Combined with high-resolution multiomic signatures, these time-based patterns are increasingly used to inform predictive models of disease risk and management.15

Aligning such interventions with cyclical environmental rhythms enables personalized medicine to achieve greater precision, tailoring treatments to daily fluctuations and seasonal trends. As a result, these advances have far-reaching implications for modern research, clinical practice, and the development of health technologies that improve disease prevention, diagnosis, and treatment.

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Ishihara, A., Courville, A.B., & Chen, K.Y. (2023). The Complex Effects of Light on Metabolism in Humans. Nutrients, 15(6):1391. DOI:10.3390/nu15061391, https://www.mdpi.com/2072-6643/15/6/1391

Wucher, V., Sodaei, R., Amador, R., Irimia, M., & Guigó, R. (2023). Day-night and seasonal variation of human gene expression across tissues. PLOS Biology, 21(2), e3001986. DOI:10.1371/journal.pbio.3001986, https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001986

Skeldon, A.C., & Dijk, D.-J. (2021). Weekly and seasonal variation in the circadian melatonin rhythm in humans: Entrained to local clock time, social time, light exposure or sun time? Journal of Pineal Research, 71(1), e12746. DOI:10.1111/jpi.12746, https://onlinelibrary.wiley.com/doi/10.1111/jpi.12746

Gassen, J., Mengelkoch, S., & Slavich, G.M. (2024). Human immune and metabolic biomarker levels, and stress-biomarker associations, differ by season: Implications for biomedical health research. Brain, Behavior, & Immunity-Health, 38:100793. DOI:10.1016/j.bbih.2024.100793, https://www.sciencedirect.com/science/article/pii/S2666354624000220

Dhawka, L., Cha, Y., Ay, A., & Ingram, K.K. (2022). Low circadian amplitude and delayed phase are linked to seasonal affective disorder (SAD). Journal of Affective Disorders Reports, 10, 100395. DOI:10.1016/j.jadr.2022.100395, https://www.sciencedirect.com/science/article/pii/S2666915322000877

Priya, E.K., Shidhi, P.R., Sreedevi, S., & Banerjee, M. (2025). Impact of seasonal cycle on rheumatoid arthritis based on genetic and epigenetic mechanisms. Frontiers in Immunology, 16, 1601767. DOI:10.3389/fimmu.2025.1601767, https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1601767/full

Makkawi, S., Aljabri, A., Bin Lajdam, G., Albakistani, A., Aljohani, A., Labban, S., & Felemban, R. (2022). Effect of Seasonal Variation on Relapse Rate in Patients With Relapsing-Remitting Multiple Sclerosis in Saudi Arabia. Frontiers in Neurology, 13, 862120. DOI:10.3389/fneur.2022.862120, https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2022.862120/full

Hachemi, I., & U-Din, M. (2023). Brown Adipose Tissue: Activation and Metabolism in Humans. Endocrinology and Metabolism, 38(2):214-222. DOI:10.3803/EnM.2023.1659, https://www.e-enm.org/journal/view.php?doi=10.3803/EnM.2023.1659

Hidalgo, S., & Chiu, J.C. (2024). Integration of photoperiodic and temperature cues by the circadian clock to regulate insect seasonal adaptations. Journal of Comparative Physiology A, 210:585-599. DOI:10.1007/s00359-023-01667-1, https://link.springer.com/article/10.1007/s00359-023-01667-1

Munley, K.M., Dutta, S., Jasnow, A.M., & Demas, G.E. (2022). Adrenal MT1 melatonin receptor expression is linked with seasonal variation in social behavior in male Siberian hamsters. Hormones and Behavior, 138:105099. DOI:10.1016/j.yhbeh.2021.105099, https://www.sciencedirect.com/science/article/pii/S0018506X21002875

Xu, Y., Jiang, D., Liu, J., Fu, Y., Song, Y., Fan, D., Huang, X., Liufu, S., Pan, J., Ouyang, H., Tian, Y., Shen, X., & Huang, Y. (2022). Photoperiodic Changes in Both Hypothalamus Neurotransmitters and Circulating Gonadal Steroids Metabolomic Profiles in Relation to Seasonal Reproduction in Male Quail. Frontiers in Physiology, 13, 824228. DOI:10.3389/fphys.2022.824228, https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2022.824228/full

Chmura, H.E., Duncan, C., Saer, B., Moore, J.T., Barnes, B.M., Buck, C.L., Christian, H.C., Loudon, A.S.I., & Williams, C.T. (2022). Hypothalamic remodeling of thyroid hormone signaling during hibernation in the arctic ground squirrel. Communications Biology, 5, 492. DOI:10.1038/s42003-022-03431-8, https://www.nature.com/articles/s42003-022-03431-8

Meier, S.A., Furrer, M., Nowak, N., Zenobi, R., Sundset, M.A., Huber, R., Brown, S.A., & Wagner, G. (2024). Uncoupling of behavioral and metabolic 24-hour rhythms in reindeer. Current Biology, 34(7):1596–1603.e4. DOI:10.1016/j.cub.2024.02.072, https://www.sciencedirect.com/science/article/pii/S0960982224002549

Baum, L., Johns, M., Poikela, M., Möller, R., Ananthasubramaniam, B., & Prasser, F. (2023). Data integration and analysis for circadian medicine. Acta Physiologica, 237(4), e13951. DOI:10.1111/apha.13951, https://onlinelibrary.wiley.com/doi/10.1111/apha.13951

Last Updated: Dec 1, 2025