Curcumin and hesperetin attenuate D-galactose-induced brain senescence in vitro and in vivo
Open accessAbstract
BACKGROUND/OBJECTIVES: Brain senescence causes cognitive impairment and neurodegeneration. It has also been demonstrated that curcumin (Cur) and hesperetin (Hes), both antioxidant polyphenolic compounds, mediate anti-aging and neuroprotective effects. Therefore, the objective of this study was to investigate whether Cur, Hes, and/or their combination exert anti-aging effects in D-galactose (Dg)-induced aged neuronal cells and rats. MATERIALS/METHODS: , brain aging was induced by injecting 250 mg/kg body weight (b.w.) Dg. The effects of supplementing this model with 50 mg/kg b.w. Cur, 50 mg/kg b.w. Hes, or a combination of both for 3 months were subsequently evaluated. Brain aging was examined with a step-through passive avoidance test and apoptosis markers were analyzed in brain cortex tissues. RESULTS: Cur, Hes, and their combination improved neuron length and cellular senescence by decreasing the number of β-gal stained cells, down-regulated expression of p16 and p21, and up-regulated expression of antioxidant enzymes, including superoxide dismutase 1, glutathione peroxidase 1, and catalase. Administration of Cur, Hes, or their combination also tended to ameliorate cognitive impairment and suppress apoptosis in the cerebral cortex by down-regulating Bax and poly (ADP-ribose) polymerase expression and increasing Bcl-2 expression. CONCLUSIONS: Cur and Hes appear to attenuate Dg-induced brain aging via regulation of antioxidant enzymes and apoptosis. These results suggest that Cur and Hes may mediate neuroprotective effects in the aging process, and further study of these antioxidant polyphenolic compounds is warranted.
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CUR has been shown to improve cognitive deficits, suppress vascular aging and inflammation in elderly mice, and attenuate neuronal aging both in vitro and in vivo by downregulating p16 and p21 and upregulating antioxidant enzymes including SOD1, CAT and GPx.
“Indeed, it has been shown to improve cognitive deficits, suppress vascular aging and inflammation in elderly mice, and attenuate neuronal aging both in vitro and in vivo by downregulating the expression of p16 and p21 and upregulating antioxidant enzymes, including SOD1, CAT and GPx [329,330,397].”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [397]
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Cellular Senescence: Molecular Targets, Biomarkers, and Senolytic Drugs
Kudlová, N., Sanctis, J. B. D., & Hajdúch, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23084168 · Cited by 176 · see citing works
The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence
Varesi, A., Chirumbolo, S., Campagnoli, L. I. M., Pierella, E., Piccini, G. B., Carrara, A., Ricevuti, G., Scassellati, C., Bonvicini, C., & Pascale, A. (2022) · Antioxidants · doi:10.3390/antiox11071224 · Cited by 145 · see citing works
“Further, CUR possesses antioxidant properties, through which it can prevent lipid peroxidation, stabilize Nrf2, with the consequent expression of HO-1, and increase the levels of antioxidant enzymes, such as SOD, GST, GSH and GPx [395].”
BackgroundInfluentialCurcumin as Prospective Anti-Aging Natural Compound: Focus on Brain
Tarek, B., Soleti, R., Panaro, M. A., Torre, M. E. L., Monda, V., Messina, G., & Porro, C. (2021) · Molecules · doi:10.3390/molecules26164794 · Cited by 100 · see citing works
“Administration of curcumin ameliorated the cognitive impairment and suppressed apoptosis in the cerebral cortex by downregulating Bax and poly (ADP-ribose) polymerase expression and increasing Bcl-2 expression [86].”
BackgroundThe Molecular Mechanism of Polyphenols with Anti-Aging Activity in Aged Human Dermal Fibroblasts
Lee, J. H., Park, J., & Shin, D. W. (2022) · Molecules · doi:10.3390/molecules27144351 · Cited by 88 · see citing works
Self-citationCurcumin: A Golden Approach to Healthy Aging: A Systematic Review of the Evidence
Nunes, Y. C., Mendes, N. M., de Lima, E. P., Chehadi, A. C., Lamas, C. B., Haber, J., Bueno, M. D. S., Araújo, A., Catharin, V. C. S., Detregiachi, C. R. P., et al. (2024) · Nutrients · doi:10.3390/nu16162721 · Cited by 63 · see citing works
“Zhi et al. [44] investigated male C57BL/6 mice with trigeminal neuralgia administered 100 mg/kg/day curcumin twice a day for 14 days to observe its effects on orofacial allodynia and cognitive impairment and showed an increase in the density of dendritic spines, and in the regulation and proportion…”
BackgroundMethodSingh, P., Barman, B., & Thakur, M. K. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.944697 · Cited by 69 · see citing works
Luís, C., Maduro, A. I., Pereira, P. M. D. C. C., Mendes, J. J., Soares, R. A., & Ramalho, R. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.958563 · Cited by 64 · see citing works
Iwasaki, K., Abarca, C., & Aguayo-Mazzucato, C. (2023) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2022.0416 · Cited by 43 · see citing works
“The combination of the antioxidant polyphenolic compounds curcumin and hesperetin has been reported to improve cellular senescence in D-galactoseinduced senescent neurons and rats, including reduced β-gal staining cell number, p16Ink4a, and p21Cip1 [91].”
BackgroundLuteolin Mitigates D-Galactose-Induced Brain Ageing in Rats: SIRT1-Mediated Neuroprotection
Younis, R. L., El‐Gohary, R. M., Ghalwash, A. A., Hegab, I. I., Ghabrial, M. M. M., Aboshanady, A. M. M., Mostafa, R. A., El‐Azeem, A. H. A., Farghal, E. E., Belal, A. A. E., et al. (2024) · Neurochemical Research · doi:10.1007/s11064-024-04203-y · Cited by 44 · see citing works
Xue, F., Li, X., Qin, L., Liu, X., Li, C., & Adhikari, B. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.113886 · Cited by 43 · see citing works
Effects of Curcumin on Aging: Molecular Mechanisms and Experimental Evidence
Bahrami, A., Montecucco, F., Carbone, F., & Sahebkar, A. (2021) · BioMed Research International · doi:10.1155/2021/8972074 · Cited by 41 · see citing works
“CUR prevents D-gal-induced brain aging and cognitive impairment through increments of antioxidant enzymes and inhibition of apoptosis [108].”
BackgroundSong, B., Hao, M., Zhang, S., Niu, W., Li, Y., Chen, Q., Li, S., & Tong, C. (2024) · Fitoterapia · doi:10.1016/j.fitote.2024.106206 · Cited by 37 · see citing works
Ji, C., Wei, C., Li, M., Shen, S., Zhang, S., Hou, Y., & Wu, Y. (2022) · Pharmaceutical Biology · doi:10.1080/13880209.2022.2131839 · Cited by 30 · see citing works
“Some natural compounds derived from herbal medicines, including fisetin, quercetin and curcumin (Lee et al. 2020), have been shown to treat cognitive deficits by eliminating senescent cells.”
BackgroundWdowiak, K., Tajber, L., Miklaszewski, A., & Cielecka‐Piontek, J. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16050659 · Cited by 23 · see citing works
“Also, the study by Lee et al. suggested the potential benefits of co-administration of both compounds [20].”
BackgroundResultArias, C., Álvarez‐Indo, J., Cifuentes, M., Morselli, E., Kerr, B., & Burgos, P. V. (2024) · Biological Research · doi:10.1186/s40659-024-00531-z · Cited by 22 · see citing works
“Due to the pleiotropic effects of SASP, natural treatments such as polyphenols could represent a therapeutic strategy, as potential game-changers in pre-clinical models [111, 112] (Fig.”
BackgroundCurcumin attenuates brain aging by reducing apoptosis and oxidative stress
Cheriki, M., Habibian, M., & Moosavi, S. J. (2024) · Metabolic Brain Disease · doi:10.1007/s11011-023-01326-z · Cited by 18 · see citing works
“Moreover, it has been shown that curcumin, may attenuate D galactose-induced brain aging via regulation of antioxidant enzymes and apoptosis (Lee et al. 2020b).”
InfluentialTrends in intestinal aging: From underlying mechanisms to therapeutic strategies
Wang, Y., Zhang, X., Qing, M., Dang, W., Bai, X., Wang, Y., Zhou, D., Zhu, L., Qing, D., Zhang, J., et al. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.05.011 · Cited by 19 · see citing works
“Additionally, it delays the aging process by enhancing antioxidant enzyme activity while inhibiting the expression of senescence-associated proteins (P16 and P21) and pepck gene 241,242 .”
Prajapat, M., Kaur, G., Choudhary, G. P., Pahwa, P., Bansal, S., Joshi, R., Batra, G., Mishra, A., Singla, R., Kaur, H., et al. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1296919 · Cited by 15 · see citing works
“Other studies by Wang et al. and Rahimi et al. suggested that exposure of 200 mM to 400 mM D-galactose to retinoic acid induced differentiated SHSY5Y cells that can cause senescence and oxidative stress by decreasing NADPH glutathione reductase (Lee et al., 2020).”
BackgroundHuman iPSC-Derived Neurons as A Platform for Deciphering the Mechanisms behind Brain Aging
Chao, C., Shen, P.-W., Tzeng, T., Kung, H., Tsai, T., & Wong, Y. (2021) · Biomedicines · doi:10.3390/biomedicines9111635 · Cited by 13 · see citing works
The effect of curcumin on blood pressure and cognitive impairment in spontaneously hypertensive rats
Lim, J. Y., Kim, W., & Ha, A. W. (2023) · Nutrition Research and Practice · doi:10.4162/nrp.2023.17.2.192 · Cited by 11 · see citing works
“Previous studies have reported similar results, despite differences in the behavioral test method or the amount of curcumin administered to animals, ranging from 20 to 300 mg/kg [26-30, 38-41].”
BackgroundMethodResultMartin, M., Boulaire, M., Lucas, C., Peltier, A., Pourtau, L., Gaudout, D., Layé, S., Pallet, V., Joffre, C., & Dinel, A. (2024) · Journal of Nutrition · doi:10.1016/j.tjnut.2024.09.015 · Cited by 9 · see citing works
Wdowiak, K., Tajber, L., Miklaszewski, A., & Cielecka‐Piontek, J. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics17010026 · Cited by 7 · see citing works
Chelidonic acid abrogates oxidative stress and memory dysfunction in experimental aging rats
Sinan, F. N., Kasikci, E., & Çevreli, B. (2024) · TURKISH JOURNAL OF BIOLOGY · doi:10.55730/1300-0152.2717 · Cited by 6 · see citing works
Decoding the neuroprotective potential of hesperidin: Insights into Alzheimer’s disease
Chauhan, P., Vadia, N., Ballal, S., Joshi, K. K., Maharana, L., Chauhan, A. S., Abomughaid, M. M., Lakhanpal, S., Avinash, D., Thakur, K., et al. (2025) · Neuroscience · doi:10.1016/j.neuroscience.2025.09.028 · Cited by 5 · see citing works
Lin, Q., Fan, W., Chen, Z., Chen, B., & Zhang, C. (2025) · The FASEB Journal · doi:10.1096/fj.202502311r · Cited by 5 · see citing works
Pintana, H., Apaijai, N., Chunchai, T., Thonusin, C., Saengmearnuparp, T., Kongkaew, A., Chattipakorn, N., & Chattipakorn, S. C. (2024) · Journal of Neuroscience Research · doi:10.1002/jnr.25389 · Cited by 5 · see citing works
Castillo-Moral, Á., Tchoumtchoua, J., Leonard, K., Bas-Prior, J. M. D., Ortega-Olivé, N., Escoté, X., & Teichenne-Jané, J. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.118776 · Cited by 4 · see citing works
Khongkla, E., Promtap, K., Meerasri, J., Mo-Mai, P., Chankamngoen, W., Sirinonthanawech, N., & Chetsawang, B. (2026) · Scientific Reports · doi:10.1038/s41598-025-34661-5 · Cited by 3 · see citing works
Talebinasab, A., Javanbakht, P., Mojaverrostami, S., Kashani, I. R., Keshavarz, L., Hashemi, M., Amirizadeh, S., Shabani, M., & Asadi-Golshan, R. (2025) · Nutritional Neuroscience · doi:10.1080/1028415x.2025.2575810 · Cited by 2 · see citing works
“Hesperidin also plays an essential role in the reduction of endoplasmic reticulum stress and apoptosis [72,73].”
Ciurleo, G. C. V., de Azevedo, O. G. R., Carvalho, C. G. M., Vitek, M. P., Warren, C. A., Guerrant, R. L., & Oriá, R. B. (2024) · Clinical Nutrition ESPEN · doi:10.1016/j.clnesp.2024.09.004 · Cited by 2 · see citing works
Ghanbari–Niaki, A., Rahmati-Ahmadabad, S., Broom, D. R., Kolbadinejad, A.-A., Nikbakht, J., & Hofmeister, M. (2022) · Brazilian Archives of Biology and Technology · doi:10.1590/1678-4324-2022210460 · Cited by 2 · see citing works
Pekker, E., Qorri, E., Enyedi, M. Z., Szukacsov, V., Ayaydin, F., Szabó-Kriston, É., Csányi, B., Mórocz, M., Sükösd, F., Kiss‐Toth, E., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-30633-x · Cited by 1 · see citing works
“…in Erk1/2 activation 79,80 , may offer unique insights into cellular aging mechanisms, while NEFH, a biomarker of neuronal differentiation 81 , which demonstrated the highest overexpression, and C1QL1, a senescence-associated gene with potential roles in neuronal differentiation 82,83 ,…”
Duarte, M., Pedrosa, S. S., Khusial, P. R., & Madureira, A. R. (2026) · Phytotherapy Research · doi:10.1002/ptr.70239 · Cited by 1 · see citing works
“…a study where senescence was induced in neuronal cells (SH-SY5Y) by exposure to D-galactose in vitro, hesperetin was found to ameliorate the cellular aging phenotype by reducing the number of SA- β-gal stained cells, as well as downregulating the expression of p16 and p21 (Lee, Kim, et al. 2020).”
Zamani, N. I. S. M., Hamezah, H. S., Mediani, A., Ghazali, M., Sadikan, M. Z., & Jam, F. A. (2026) · Scientific Reports · doi:10.1038/s41598-026-53311-y · Cited by 1 · see citing works
Habibian, M., & Moosavi, S. J. (2023) · Preprints.org · doi:10.20944/preprints202302.0290.v1 · Cited by 1 · see citing works
Molecular Mechanisms Behind Organ-Related Aging and Regulatory Effects of Natural Therapeutics
Abaidullah, R., Ali, S., Summer, M., & Tahir, H. (2025) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-025-01792-5
de Almeida, A. J. P. O., Pontes, L. V. D. S., Júnior, J. F. D. S., Soares, E. M. C., dos Santos, A. C., Gonçalves, T. A. F., Feitosa, M. S. D. A., Veras, R. C., Barbosa‐Filho, J. M., Lesniewski, L. A., et al. (2026) · Molecules · doi:10.3390/molecules31101614
“Moreover, the D-galactose senescence model shows elevated levels of p16, p21, and p53, as well as elevated DNA damage (e.g., γ -H2AX) [21,23].”
Blomquist, S. A., Kelly, G., D’Adamo, C. R., Han, C., Parker, H., Adães, S., Gardner, C. R., Ardagh, A., Ramer, S., & Scuba, W. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27104406 · Cited by 1 · see citing works
“Additional phytochemicals in the formula predominantly exhibit senomorphic activity, modulating inflammatory and stress-response pathways like NF-κ B, p38 MAPK, cGAS–STING, JNK, and lysosomal β -galactosidase activity, with context-dependent senolytic effects in specific models [70–82].”
Mouafon, I. L., Ebede, G. R., Bella, M. A., Katerere, D. R., Njock, G. B. B., & Ndongo, J. T. (2026) · Springer eBooks · doi:10.1007/978-981-95-8064-4_14
Hussin, N. M. H., Mediani, A., Latip, N. A., Fenech, M. F., Widyanto, R. M., & Sharif, R. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27167181
“Curcumin combined with hesperetin further produced dual senomorphic and senolytic activity in senescent neuronal cells, in both in vitro and in vivo studies, for neurodegeneration-associated senescence [74].”
- Authors
- Lee, J., Kim, Y. S., Kim, E., Kim, Y., & Kim, Y.
- Affiliations
- Ewha Womans University (KR)
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 03760, Korea.
- Venue
- Nutrition Research and Practice
- Publisher
- XMLink
- Published
- 2020
- Volume
- 14
- Issue
- 5
- Pages
- 438
- ISSN
- 1976-1457 (ISSN-L)
- 2005-6168
- PMC
- PMC7520561
- OpenAlex
- W3047795840
- Cited by
- 41
- References
- 72
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 12 · 2023: 4 · 2022: 7 · 2021: 4
- FWCI
- 1.72
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- Locations
- Nutrition Research and Practice (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Ottogi Ham Taiho Foundation (22A20130012143)
- Brain Korea 21 Plus
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Antioxidants, Aging, Portulaca oleracea
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Curcumin's Biomedical Applications
- Health Sciences › Medicine › Biochemistry › Phytochemicals and Antioxidant Activities
- Keywords
- curcumin, hesperetin, brain aging, D-galactose-induced aging, neuroprotection, antioxidant polyphenols, apoptosis, cognitive impairment, cerebral cortex, beta-galactosidase, p16, p21, Bax, Bcl-2, superoxide dismutase 1, glutathione peroxidase 1, catalase, combination therapy
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