Sains Malaysiana 55(3)(2026): 475-489

http://doi.org/10.17576/jsm-2026-5503-10

Liver Metabolite Profiles and Oxidative Stress in Ageing Rats and Their Modulation by Tocotrienol-Rich Fraction

(Profil Metabolit Hati dan Tekanan Oksidatif pada Tikus yang Semakin Tua dan Modulasinya oleh Fraksi Kaya-Tokotrienol)

ANIKA TABASSUM¹, SITI LIYANA SAUD GANY¹, JEN KIT TAN^1,2 & SUZANA MAKPOL^1,2,*

¹Department of Biochemistry, Faculty of Medicine, Level 17 Preclinical Building, Universiti Kebangsaan, Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, 56000 Kuala Lumpur, Malaysia

²Ageing and Degenerative Diseases Research Group, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor, Malaysia

Received: 25 September 2025/Accepted: 19 February 2026

Abstract

Ageing alters liver metabolism and function, accompanied by morphological changes in hepatic cells, including disrupted metabolite profiles and structural degeneration. These changes contribute to increased oxidative stress and inflammation. However, the connection between oxidative stress, inflammation, histological changes, and liver metabolism during ageing, and the potential of the tocotrienol-rich fraction (TRF) as a therapeutic agent, remains underexplored. This study investigates age-related hepatic changes and the effects of TRF using metabolomics. Sprague-Dawley rats aged 3, 9, and 21 months were assigned to control and treatment groups and received either palm olein or TRF supplementation. Liver tissues were analysed using untargeted metabolomics via LC-MS/MS, along with histological evaluation and biochemical assessments of antioxidant enzymes (SOD, CAT), inflammatory markers (IL-6, TNF-alpha), and lipid peroxidation markers (MDA). SOD activity declined significantly with age in both control and TRF-treated old rats (p<0.05), suggesting reduced antioxidant defence with increasing age, whereas no significant changes were observed in CAT, IL-6 or MDA levels. Histologically, TRF-treated livers displayed fewer fibroblasts and less inflammation than control livers. Metabolomics showed age-related alterations in taurine and hypotaurine metabolism, pyrimidine metabolism (uridine and uracil), and TCA cycle components (malate and glutamate). These findings demonstrate that TRF modulates age-related liver changes, particularly in morphology and metabolism, despite a persistent decline in antioxidant activity. This finding underscores the potential of TRF in mitigating liver ageing. It provides insight into key metabolic pathways involved, offering a foundation for future therapeutic strategies targeting liver health in the elderly.

Keywords: Hepatic ageing; liver; metabolomics; oxidative stress; tocotrienol-rich fraction

Abstrak

Penuaan mendorong perubahan dalam metabolisme dan fungsi hati, disertai dengan perubahan morfologi dalam sel hepatik seperti profil metabolit yang terganggu dan degenerasi struktur. Perubahan ini menyumbang kepada peningkatan tekanan oksidatif dan keradangan. Walau bagaimanapun, hubungan antara tekanan oksidatif, keradangan, perubahan histologi dan metabolisme hati semasa penuaan dan potensi fraksi kaya-tokotrienol (TRF) sebagai agen terapeutik masih kurang diterokai. Penyelidikan ini mengkaji perubahan hepatik yang berkaitan dengan usia dan kesan TRF menggunakan pendekatan omik lanjutan. Tikus Sprague-Dawley berumur 3, 9 dan 21 bulan dibahagikan kepada kumpulan kawalan dan rawatan, menerima sama ada olein kelapa sawit atau suplemen TRF. Tisu hati dianalisis menggunakan metabolomik yang tidak disasarkan melalui LC-MS/MS, bersama-sama dengan penilaian histologi dan penilaian biokimia enzim antioksidan (SOD, CAT), penanda keradangan (IL-6,TNF-alpha) dan peroksidasi lipid (MDA). Aktiviti SOD merosot dengan ketara dengan umur dalam kedua-dua kawalan dan tikus yang dirawat TRF (p<0.05), mencadangkan pengurangan pertahanan antioksidan dengan peningkatan umur, manakala tiada perubahan ketara diperhatikan dalam tahap CAT, IL-6 atau MDA. Secara histologi, hati yang dirawat TRF menunjukkan lebih sedikit fibroblas dan kurang keradangan daripada hati kawalan. Metabolomik mendedahkan perubahan berkaitan usia dalam metabolisme taurin dan hipotaurin, metabolisme pirimidin (uridin dan uracil) dan komponen kitaran TCA (malat dan glutamat). Penemuan ini menunjukkan bahawa TRF memodulasi beberapa aspek perubahan hati yang berkaitan dengan usia, terutamanya dalam morfologi dan metabolisme, walaupun penurunan antioksidan yang berterusan. Hasil kajian ini menggariskan potensi TRF dalam mengurangkan penuaan hati dan memberikan gambaran tentang laluan metabolik utama yang terlibat, menawarkan asas untuk strategi terapeutik masa hadapan yang menyasarkan kesihatan hati dalam kalangan warga tua.

Kata kunci: Fraksi kaya-tokotrienol; hati; metabolomik; penuaan hepatik; tekanan oksidatif

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*Corresponding author; email: suzanamakpol@ukm.edu.my