This article is about autophagy and senescence, critical biological processes, and their roles in aging, health and wellness. It’s also about spermidine and fisetin, two naturally occurring compounds, and their role in promoting autophagy and reducing senescence. Let’s start with autophagy.
Autophagy
Autophagy (pronounced “ah-TAH-fah-gee”) is the body’s process of breaking down old and damaged cell parts. This allows cells to disassemble junk parts and repurpose the salvageable components into new, usable cell parts, while discarding the unusable or unneeded parts. In addition, autophagy works as cellular quality control. Essentially, an excess of junk components in a cell takes up space and can slow or prevent a cell from functioning correctly. Autophagy helps eliminate cellular clutter, optimizing cellular performance. Furthermore, autophagy also plays an important role when it comes to healthy aging. As a person ages, autophagy decreases, which can lead to a build-up of cellular junk parts and, in turn, cells that aren’t functioning at their best.1
Autophagy and Aging
As a person ages, autophagy decreases, which can lead to a build-up of cellular junk parts and, in turn, cells that aren’t functioning at their best. The mechanisms by which this occurs is that impaired autophagy promotes accumulation of senescence-associated proteins and dysfunctional organelles, energy imbalance and reactive oxygen species (ROS) accumulation, aggregated protein (e.g., tau, α-synuclein) accumulation in neurons, limited stem cell maintenance and regenerative capacity, and altered immune cell function.2-4
Introduction to Polyamines
Polyamines, including spermidine, spermine and putrescine, are synthesized in every living cell and are contained in foods, especially in those considered to contribute to health and longevity. They have many physiological activities similar to polyphenols, such as antioxidant and anti-inflammatory properties, cell and gene protection, and autophagy activation. Research has reported that increased polyamine intake (primarily spermidine) over a long period increased blood spermine levels and inhibited aging-associated pathologies and pro-inflammatory status in humans and mice, while also extended life span of mice.5
Spermidine and Autophagy
Spermidine has been shown to increase autophagy.6-9 In a follow-up study of a cohort of 829 participants for 20 years, spermidine showed the strongest inverse relation with mortality among 146 nutrients investigated. This effect was dose-dependent, and the authors explain that spermidine effectively induced autophagy and can reduce the acetylation of histones, which are critical processes for cell homeostasis in aging. In this sense, a diet rich in spermidine, mainly from foods of vegetable origin, was associated with a decrease in the risk of all-cause mortality in the general community.10
Heretofore, the research on spermidine and autophagy has been limited to in-vitro, animal and epidemiological studies rather than human clinical studies. As such, there was no answer to the question, “How much spermidine is needed to induce autophagy?”
A Clinical Study on Miricell Rice Germ Polyamines
That question was examined in a 56-day, single-blinded, proof-of-concept pilot study conducted by the Center for Applied Health Sciences (CAHS),11 which included the administration of 3.3. mg of spermidine from Miricell rice germ extract (a natural, non-GMO, allergen-free, vegan friendly, rice-derived source of spermidine with other naturally occurring polyamines, offered by Nutraland USA) to healthy adult subjects, aged 30-65. This study examined two markers of autophagy—Beclin-1 and ULK-1—as well as a few other markers associated with cognitive health and cardiometabolic health. The results were both groundbreaking and meaningful.
Beclin-1 and ULK-1
It is understood that fasting increases autophagy. This has been demonstrated in research12 where prolonged intermittent fasting increased Beclin-1 by 13.3 percent within two weeks. The current clinical study on Miricell showed that 3.3 mg dose of spermidine from Miricell resulted in a 7.25 percent increase in Beclin-1 compared to baseline. Likewise, the 3.3 mg dose of spermidine resulted in a 13.36 percent increase in ULK-1. To the best of my knowledge and at the time of this writing, this dose of spermidine from Miricell is the only spermidine clinically demonstrated to effectively increase markers of autophagy.
Brain-derived Neurotrophic Factor (BDNF)
In addition, the Miricell study also measured BDNF, a key molecule in the body that plays an important role in nerve survival and growth, serves as a neurotransmitter modulator, and participates in neuronal plasticity (i.e., adaptability to changes in environment), which is essential for learning and memory including long-term memory.13 The 3.3 mg dose of spermidine from Miricell resulted in a 12.05 percent increase in BDNF compared to baseline.14
In addition to the markers of autophagy and BDNF, this pilot study also examined cardiometabolic markers including hs-CRP, VLDL and triglycerides.
High-sensitivity C-reactive Protein (hs-CRP)
hs-CRP is a protein in the blood that increases in response to inflammation. Hence, it serves as an inflammatory marker.15 In the current study, the 3.3 mg dose of spermidine from Miricell resulted in a 20.83 percent decrease in hs-CRP compared to baseline.
Very Low-density Lipoprotein (VLDL)
VLDL is a type of lipoprotein that carries triglycerides and other fats in the bloodstream. It’s produced by the liver and is considered a type of “bad cholesterol” because it can contribute to plaque buildup in the arteries.16 In the current study, the 3.3 mg dose of spermidine from Miricell likewise resulted in a 20.05 percent decrease in VLDL compared to baseline.
Triglycerides
Triglycerides are a type of fat (lipid) found in the bloodstream. In addition to being a marker for metabolic syndrome, high levels can increase the risk of heart disease, stroke and pancreatitis.17 Again, some nutraceuticals have been shown to reduce triglyceride levels. In the current study, the 3.3 mg dose of spermidine from Miricell resulted in a 26.9 percent decrease in triglycerides.
Senescence
Senescence is a biological process in which cells permanently stop dividing and enter a state of growth arrest, without undergoing cell death. In short, senescence is cellular deterioration with age. In fact, senescence contributes to chronic disease and aging.18 Cellular senescence involves cell-cycle arrest and the release of inflammatory cytokines with autocrine, paracrine and endocrine activities. Senescent cells also exhibit morphological alterations, including flattened cell bodies, vacuolization and granularity in the cytoplasm and abnormal organelles. Several biomarkers of cellular senescence have been identified, including SA-βgal, p16 and p21. Luckily, there are senolytic agents that have been shown to extend lifespan and reduce tissue injury.19
Introduction to Fisetin
Flavonoids are a broadly distributed class of compounds regularly consumed in the diet. One such flavonoid, fisetin (3,3′,4′,7-tetrahydroxyflavone), is found in various fruits and vegetables, such as strawberry, apple, persimmon, grape, onion and cucumber. Fisetin has been reported to have neurotrophic, anticarcinogenic, anti-inflammatory, and other beneficial health effects, including that as a senolytic agent.20
Fisetin and Synolysis
In one study,21 a panel of flavonoid polyphenols was screened for senolytic activity using senescent murine and human fibroblasts, driven by oxidative and genotoxic stress, respectively. Of the 10 flavonoids tested, fisetin was the most potent senolytic. Acute or intermittent treatment of progeroid and old mice with fisetin reduced senescence markers in multiple tissues, consistent with a hit-and-run senolytic mechanism. Fisetin reduced senescence in a subset of cells in murine and human adipose tissue, demonstrating cell-type specificity. Administration of fisetin to wild-type mice late in life restored tissue homeostasis, reduced age-related pathology and extended median and maximum lifespan. Other studies22-24 have shown similar senolytic results with fisetin.
Fisetin in Human Research
In a recent cohort study,25,26 a sub-analysis of healthy participants (n=10) reporting daily self-dosing of 100 mg/day fisetin showed a decrease in serum levels of SASP factors (MMP-3, MMP-9, platelet-derived growth factor AA [PDGF-AA], IL-6 and ‐8, monocyte chemoattractant protein-1 [MCP-1] and GDF11 and ‐15) between the baseline and a follow-up visit The study also reported a decrease in the percentage of senescent (C12FDG++ bright, co-expressing uPAR) peripheral blood mononuclear cells (PBMCs).
In addition, there has been human research on fisetin showing other benefits:
• In a randomized, controlled trial (RCT) with stroke patients, 100 mg/day fisetin dramatically improved stroke outcome which was likely attributable to reduced levels of MMP-2, MMP-9, and CRP in the serum.27 These biomarkers are associated with inflammation.
• In another RCT, 100 mg/day fisetin reduced the inflammatory markers IL-8 and hs-CRP and suppressed the values of MMP-7 levels in colorectal cancer patients.28
Conclusion
Autophagy is a critical biological process to help rejuvenate and optimizing cellular performance, while senescence is cellular deterioration with age. Since autophagy declines with aging, it may make sense to supplement with spermidine from Miricell rice germ extract which has been shown in human clinical research to promote autophagy as well as improve cardiometabolic markers. Likewise, it makes sense to utilize fisetin as a senolytic agent to reduce senescence. The combination of both may offer additive benefits in the quest to promote a healthy lifespan.VR
References
1 Autophagy. Cleveland Clinic. Last reviewed by a Cleveland Clinic medical professional on 08/23/2022. Retrieved May 24, 2023 from https://my.clevelandclinic.org/health/articles/24058-autophagy#:~:text=Autophagy percent20allows percent20your percent20body percent20to,potentially percent20preventing percent20and percent20fighting percent20disease.
2 Cheon SY, Kim H, Rubinsztein DC, Lee JE. Autophagy, Cellular Aging and Age-related Human Diseases. Exp Neurobiol. 2019 Dec 31;28(6):643-657. doi: 10.5607/en.2019.28.6.643. PMID: 31902153; PMCID: PMC6946111. 3 Metaxakis A, Ploumi C, Tavernarakis N. Autophagy in Age-Associated Neurodegeneration. Cells. 2018; 7(5):37. https://doi.org/10.3390/cells7050037.
4 Cheon SY, Kim H, Rubinsztein DC, Lee JE. Autophagy, Cellular Aging and Age-related Human Diseases. Exp Neurobiol. 2019 Dec 31;28(6):643-657. doi: 10.5607/en.2019.28.6.643. PMID: 31902153; PMCID: PMC6946111.
5 Soda K. Overview of Polyamines as Nutrients for Human Healthy Long Life and Effect of Increased Polyamine Intake on DNA Methylation. Cells. 2022 Jan 4;11(1):164.
6 Handa AK, Fatima T, Mattoo AK. Polyamines: bio-molecules with diverse functions in plant and human health and disease. Front Chem. 2018; 6:10.
7 Eisenberg T, Knauer H, Schauer A, Buttner S, Ruckenstuhl C, Carmona-Gutierrez D, et al. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. 2009; 11:1305–14.
8 Kiechl S, Pechlaner R, Willeit P, Notdurfter M, Paulweber B, Willeit K, et al. Higher spermidine intake is linked to lower mortality: a prospective population-based study. Am J Clin Nutr. 2018; 108:371–80.
9 Soda K. Spermine and gene methylation: a mechanism of lifespan extension induced by polyamine-rich diet. Amino Acids. 2020 Feb;52(2):213-224.
10 Kiechl S, Pechlaner R, Willeit P, Notdurfter M, Paulweber B, Willeit K, et al. Higher spermidine intake is linked to lower mortality: a prospective population-based study. Am J Clin Nutr. 2018; 108:371–80.
11 Bruno G, La Monica M, Ziegenfuss TN. Effects of Spermidine-Rich Rice Germ Extract Supplement on Biomarkers of Healthy Aging and Autophagy-Proof-of-Concept Pilot Study. Altern Ther Health Med. 2025 Oct;31(6):9-13. PMID: 40862848.
12 Erlangga Z, Ghashang SK, Hamdan I, et al. The effect of prolonged intermittent fasting on autophagy, inflammasome and senescence genes expressions: An exploratory study in healthy young males. Human Nutrition & Metabolism. 2023; 32 (2023): 200189. https://doi.org/10.1016/j.hnm.2023.200189.
13 Bathina S, Das UN. Brain-derived neurotrophic factor and its clinical implications. Arch Med Sci. 2015 Dec 10;11(6):1164-78.
14 Bekinschtein P, Cammarota M, Katche C, Slipczuk L, Rossato JI, Goldin A, Izquierdo I, Medina JH. BDNF is essential to promote persistence of long-term memory storage. Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2711-6.
15 C-reactive protein. MedlinePlus. National Library of Medicine. Retrieved January 6, 2025 from https://medlineplus.gov/ency/article/003356.htm.
16 VLDL Cholesterol. MedlinePlus. National Library of Medicine. Retrieved January 6, 2025 from https://medlineplus.gov/vldlcholesterol.html#:~:text=What percent20is percent20VLDL percent20cholesterol?,disease percent20and percent20other percent20heart percent20diseases.
17 Triglycerides. MedlinePlus. National Library of Medicine. Retrieved January 6, 2025 from https://medlineplus.gov/triglycerides.html.
18 Cummings SR, Lui LY, Zaira A, Mau T, Fielding RA, Atkinson EJ, Patel S, LeBrasseur N. Biomarkers of cellular senescence and major health outcomes in older adults. Geroscience. 2025 Jun;47(3):3407-3415. doi: 10.1007/s11357-024-01474-9. Epub 2024 Dec 18. Erratum in: Geroscience. 2025 Aug;47(4):6117. doi: 10.1007/s11357-025-01619-4. PMID: 39695064; PMCID: PMC12181601.
19 Huang, W., Hickson, L. T. J., Eirin, A., Kirkland, J. L., & Lerman, L. O. (2022). Cellular senescence: the good, the bad and the unknown. Nature Reviews Nephrology, 18(10), 611-627. https://doi.org/10.1038/s41581-022-00601-z.
20 Khan N, Syed DN, Ahmad N, Mukhtar H. Fisetin: a dietary antioxidant for health promotion. Antioxid Redox Signal. 2013 Jul 10;19(2):151-62. doi: 10.1089/ars.2012.4901. Epub 2012 Dec 18. PMID: 23121441; PMCID: PMC3689181.
21 Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, Xu M, Ling YY, Melos KI, Pirtskhalava T, Inman CL, McGuckian C, Wade EA, Kato JI, Grassi D, Wentworth M, Burd CE, Arriaga EA, Ladiges WL, Tchkonia T, Kirkland JL, Robbins PD, Niedernhofer LJ. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018 Oct;36:18-28. doi: 10.1016/j.ebiom.2018.09.015. Epub 2018 Sep 29. PMID: 30279143; PMCID: PMC6197652.
22 Mahoney SA, Venkatasubramanian R, Darrah MA, Ludwig KR, VanDongen NS, Greenberg NT, Longtine AG, Hutton DA, Brunt VE, Campisi J, Melov S, Seals DR, Rossman MJ, Clayton ZS. Intermittent supplementation with fisetin improves arterial function in old mice by decreasing cellular senescence. Aging Cell. 2024 Mar;23(3):e14060. doi: 10.1111/acel.14060. Epub 2023 Dec 7. PMID: 38062873; PMCID: PMC10928570.
23 Ji XM, Dong XX, Li JP, Tai GJ, Qiu S, Wei W, Silumbwe CW, Damdinjav D, Otieno JN, Li XX, Xu M. Fisetin Clears Senescent Cells Through the Pi3k-Akt-Bcl-2/Bcl-xl Pathway to Alleviate Diabetic Aortic Aging. Phytother Res. 2025 Apr 21. doi: 10.1002/ptr.8507. Epub ahead of print. PMID: 40259678.
24 Tavenier J, Nehlin JO, Houlind MB, Rasmussen LJ, Tchkonia T, Kirkland JL, Andersen O, Rasmussen LJH. Fisetin as a senotherapeutic agent: Evidence and perspectives for age-related diseases. Mech Ageing Dev. 2024 Dec;222:111995. doi: 10.1016/j.mad.2024.111995. Epub 2024 Oct 9. PMID: 39384074.
25 Hambright WS, Duke VR, Goff AD, Goff AW, Minas LT, Kloser H, Gao X, Huard C, Guo P, Lu A, Mitchell J, Mullen M, Su C, Tchkonia T, Espindola Netto JM, Robbins PD, Niedernhofer LJ, Kirkland JL, Bahney CS, Philippon M, Huard J. Clinical validation of C12FDG as a marker associated with senescence and osteoarthritic phenotypes. Aging Cell. 2024 May;23(5):e14113. doi: 10.1111/acel.14113. Epub 2024 May 6. PMID: 38708778; PMCID: PMC11113632.
26 O’hara K, Mullen M, Oberlohr V. et al. Poster 125: Determining Biological Age and Prolonging the Healthspan by Targeting Senescence. Orthop. J. Sports Med. 2022;10: Article 2325967121S00686, 27 Wang L, Cao D, Wu H, Jia H, Yang C, Zhang L. Fisetin Prolongs Therapy Window of Brain Ischemic Stroke Using Tissue Plasminogen Activator: A Double-Blind Randomized Placebo-Controlled Clinical Trial. Clin Appl Thromb Hemost. 2019 Jan-Dec;25:1076029619871359. doi: 10.1177/1076029619871359. PMID: 31434498; PMCID: PMC6829632.
28 Farsad-Naeimi A , Alizadeh M , Esfahani A , Darvish Aminabad E . Effect of fisetin supplementation on inflammatory factors and matrix metalloproteinase enzymes in colorectal cancer patients. Food Funct. 2018 Apr 25;9(4):2025-2031. doi: 10.1039/c7fo01898c. PMID: 29541713.
Gene Bruno, DBM, MS, RH(AHG) Professor Emeritus of Nutraceutical Science, is a writer, educator and a nutraceutical scientist with more than 45 years of experience educating natural product retailers and health care professionals and formulating natural products for dozens of dietary supplement companies. He has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines and peer-reviewed publications. Bruno also hosts “The Vitamin Professor Podcast” brought to you by VRM Media. He can be reached at [email protected].
