Exploratory functional, histological, and biochemical outcomes following OctaAge administration in naturally aged female Diannan small-ear pigs
Anti-aging interventions increasingly aim to modify more than one biological process, yet most candidates are still tested first in short-lived models, leaving limited information from naturally aged large animals. We evaluated OctaAge (an eight-component anti-aging formulation containing L-theanine, calcium alpha-ketoglutarate, resveratrol, quercetin, fisetin, apigenin, magnesium bisglycinate, and spermidine) in 11 female Diannan small-ear pigs aged 7–8 years. After a one-month acclimation period, pigs were allocated, without a random sequence and using age and body weight for balance, to a concurrent feed-control group or three months of OctaAge administration. Cardiac function and body weight were monitored longitudinally; endpoint analyses included behavioral changes, organ coefficients, femoral quantitative ultrasound measurements, intervertebral disc morphology, serum chemistry, and histological findings. OctaAge-treated pigs showed higher ejection fraction and fractional shortening, greater open-field exploration, and a higher T-maze correct-choice rate than the control group. Histological analyses showed lower cardiac collagen content and cardiomyocyte cross-sectional area, lower liver and kidney collagen content, higher hippocampal Nissl-positive area, and larger skeletal-muscle fiber cross-sectional area in OctaAge-treated pigs. Femoral quantitative ultrasound measurements were also higher in OctaAge-treated pigs, whereas body-weight trajectories were similar between groups. Renal chemistry, glucose, and lipid measures did not change significantly. OctaAge administration was therefore associated with differences in selected aging-related functional and histological parameters in this naturally aged pig cohort. Given the non-randomized design, small sample size, and multiple exploratory endpoints, the findings require confirmation in a prespecified, adequately powered study.
- López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The Hallmarks of Aging. Cell. 2013;153(6):1194-1217. doi: 10.1016/j.cell.2013.05.039
- López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023;186(2):243-278. doi: 10.1016/j.cell.2022.11.001
- Kroemer G, Maier AB, Cuervo AM, et al. From geroscience to precision geromedicine: Understanding and managing aging. Cell. 2025;188(8):2043-2062. doi: 10.1016/j.cell.2025.03.011
- Kennedy BK, Berger SL, Brunet A, et al. Geroscience: Linking Aging to Chronic Disease. Cell. 2014;159(4):709-713. doi: 10.1016/j.cell.2014.10.039
- Campisi J, Kapahi P, Lithgow GJ, Melov S, Newman JC, Verdin E. From discoveries in ageing research to therapeutics for healthy ageing. Nature. 2019;571(7764):183-192. doi: 10.1038/s41586-019-1365-2
- Partridge L, Deelen J, Slagboom PE. Facing up to the global challenges of ageing. Nature. 2018;561(7721):45-56. doi: 10.1038/s41586-018-0457-8
- Colman RJ, Anderson RM, Johnson SC, et al. Caloric Restriction Delays Disease Onset and Mortality in Rhesus Monkeys. Science. 2009;325(5937):201-204. doi: 10.1126/science.1173635
- Mattison JA, Colman RJ, Beasley TM, et al. Caloric restriction improves health and survival of rhesus monkeys. Nat Commun. 2017;8(1):14063.doi: 10.1038/ncomms14063
- Swindle MM, Makin A, Herron AJ, Clubb FJ Jr, Frazier KS. Swine as Models in Biomedical Research and Toxicology Testing. Vet Pathol. 2011;49(2):344-356. doi: 10.1177/0300985811402846
- Crick SJ, Sheppard MN, Ho SY, Gebstein L, Anderson RH. Anatomy of the pig heart: comparisons with normal human cardiac structure. Journal of Anatomy. 1998;193(1):105-119. doi: 10.1046/j.1469-7580.1998.19310105.x
- Perleberg C, Kind A, Schnieke A. Genetically engineered pigs as models for human disease. Dis Model Mech. 2018;11(1):dmm030783.doi: 10.1242/dmm.030783
- Fanjul V, Jorge I, Camafeita E, et al. Identification of common cardiometabolic alterations and deregulated pathways in mouse and pig models of aging. Aging Cell. 2020;19(9):e13203.doi: 10.1111/acel.13203
- Chin RM, Fu X, Pai MY, et al. The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature. 2014;510(7505):397-401. doi: 10.1038/nature13264
- Asadi Shahmirzadi A, Edgar D, Liao CY, et al. Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice. Cell Metabolism. 2020;32(3):447-456.e6. doi: 10.1016/j.cmet.2020.08.004
- Eisenberg T, Abdellatif M, et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. 2016;22(12):1428-1438. doi: 10.1038/nm.4222
- Madeo F, Eisenberg T, Pietrocola F, Kroemer G. Spermidine in health and disease. Science. 2018;359(6374):eaan2788.doi: 10.1126/science.aan2788
- Kiechl S, Pechlaner R, Willeit P, et al. Higher spermidine intake is linked to lower mortality: a prospective population-based study. The American Journal of Clinical Nutrition. 2018;108(2):371-380. doi: 10.1093/ajcn/nqy102
- Baur JA, Pearson KJ, Price NL, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444(7117):337-342. doi: 10.1038/nature05354
- Pearson KJ, Baur JA, Lewis KN, et al. Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span. Cell Metabolism. 2008;8(2):157-168. doi: 10.1016/j.cmet.2008.06.011
- Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015;14(4):644-658. doi: 10.1111/acel.12344
- Xu M, Pirtskhalava T, Farr JN, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med. 2018;24(8):1246-1256. doi: 10.1038/s41591-018-0092-9
- Yousefzadeh MJ, Zhu Y, McGowan SJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018;36:18-28. doi: 10.1016/j.ebiom.2018.09.015
- Perrott KM, Wiley CD, Desprez PY, Campisi J. Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells. GeroScience. 2017;39(2):161-173. doi: 10.1007/s11357-017-9970-1
- Salehi B, Venditti A, Sharifi-Rad M, et al. The Therapeutic Potential of Apigenin. IJMS. 2019;20(6):1305. doi: 10.3390/ijms20061305
- Baba Y, Inagaki S, Nakagawa S, Kaneko T, Kobayashi M, Takihara T. Effects of L-Theanine on Cognitive Function in Middle-Aged and Older Subjects: A Randomized Placebo-Controlled Study. Journal of Medicinal Food. 2021;24(4):333-341. doi: 10.1089/jmf.2020.4803
- Hidese S, Ogawa S, Ota M, et al. Effects of L-Theanine Administration on Stress-Related Symptoms and Cognitive Functions in Healthy Adults: A Randomized Controlled Trial. Nutrients. 2019;11(10):2362. doi: 10.3390/nu11102362
- Barbagallo M, Veronese N, Domínguez LJ. Magnesium in Aging, Health and Diseases. Nutrients. 2021;13(2):463. doi: 10.3390/nu13020463
- Percie du Sert N, Hurst V, Ahluwalia A, et al. The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. PLoS Biol. 2020;18(7):e3000410. doi: 10.1371/journal.pbio.3000410
- Ekser B, Gridelli B, Cooper DKC. Porcine alanine transaminase after liver allo‐and xenotransplantation. Xenotransplantation. 2012;19(1):52-55. doi: 10.1111/j.1399-3089.2011.00686.x
- Frangogiannis NG. Cardiac fibrosis: Cell biological mechanisms, molecular pathways and therapeutic opportunities. Molecular Aspects of Medicine. 2019;65:70-99. doi: 10.1016/j.mam.2018.07.001
- Steenman M, Lande G. Cardiac aging and heart disease in humans. Biophys Rev. 2017;9(2):131-137. doi: 10.1007/s12551-017-0255-9
- Mishra S, Kass DA. Cellular and molecular pathobiology of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2021;18(6):400-423. doi: 10.1038/s41569-020-00480-6
- Wyss-Coray T. Ageing, neurodegeneration and brain rejuvenation. Nature. 2016;539(7628):180-186. doi: 10.1038/nature20411
- Sato Y, Yanagita M. Immunology of the ageing kidney. Nat Rev Nephrol. 2019;15(10):625-640. doi: 10.1038/s41581-019-0185-9
- Li L, Fu H, Liu Y. The fibrogenic niche in kidney fibrosis: components and mechanisms. Nat Rev Nephrol. 2022;18(9):545-557. doi: 10.1038/s41581-022-00590-z
- Maeso-Díaz R, Ortega-Ribera M, Lafoz E, et al. Aging Influences Hepatic Microvascular Biology and Liver Fibrosis in Advanced Chronic Liver Disease. Aging and disease. 2019;10(4):684. doi: 10.14336/ad.2019.0127
- Lang T, Streeper T, Cawthon P, Baldwin K, Taaffe DR, Harris TB. Sarcopenia: etiology, clinical consequences, intervention, and assessment. Osteoporos Int. 2010;21(4):543-59.doi: 10.1007/s00198-009-1059-y
- Reid IR. A broader strategy for osteoporosis interventions. Nat Rev Endocrinol. 2020;16(6):333-339. doi: 10.1038/s41574-020-0339-7
