KINETIN: THE ELIXIR OF LIFE?

In a department store the other day, as I diverted my eyes from the heavily rouged women with the free samples of cologne, I was surprised to see the word “kinetin” enter into my field of vision. What were boxes of kinetin lotions doing amid all these cosmetics I wondered? One of the boxes claimed that its contents contained kinetin, “an anti-aging discovery found in green leafy plants and recommended by dermatologists. It has been clinically proven to deliver dramatic results without the irritating side effects or sun sensitivity associated with retinoids and alpha-hydroxy acids. This lotion helps reverse, delay and prevent visible signs of skin aging and sun damage while maximizing skin's ability to retain moisture. Unlike topical exfoliation with acids, this unique kinetin formula works deep within the skin's surface layers to produce dramatic results without irritation.” Skeptical, I went to the original literature and found that kinetin does, indeed, appear to be a powerful natural anti-oxidant with anti-ageing effects (Weinstein et al., 1997; Rattan, 2002). Kinetin appears to have pluripotent effects in protecting DNA and protein from oxidative and glyoxidative damage.

Kinetin: An Artifact?

Although kinetin (N-6-furfuryladenine) was the first cytokinin to be isolated (Miller et al., 1955), its source (autoclaved DNA) suggested initially that it might not be a natural compound. More recently, kinetin has been detected in commercially available DNA, in freshly extracted cellular DNA from human cells, and in plant cell extracts (Barciszewski et al., 1997). It has been suggested that kinetin is associated with plant DNA and is synthesized as a secondary product of DNA oxidation (Barciszewski et al., 2000b). Most of the experimental data point toward kinetin acting as a strong antioxidant in vitro and in vivo. Indeed, kinetin has been found to inhibit oxidative and glycoxidative protein-damage generated in vitro (Verbeke et al., 2000) and protects DNA against oxidative damage mediated by the Fenton reaction (Olsen et al., 1999).

Kinetin Delays Onset of Fibroblast Ageing

Like several other N⁶-substitured purine cytokinins, N⁶-furfuryladenine (kinetin) retards senescence in plants (Barciszewski et al., 2000a). Rattan and Clark (1994) observed that an addition of 40 to 200 μm kinetin in the culture medium of human fibroblasts both delayed the onset and decreased the extent of many of the ageing characteristics that appear during serial passaging of normal cells in culture. These effects were most pronounced in cultures in which kinetin was present continuously on the culture medium. Upon removal of kinetin, some ageing characteristics began to reappear within a few population doublings. Age-related changes that are affected by kinetin include morphological alterations, growth rates, cell size, cytoskeletal organization, macromolecular synthesis, and the intensity of autofluorescence due to the senescence-related compound lipofuscin. Although many anti-ageing factors promote carcinogenesis, this is not the case with kinetin in this in vitro system: The anti-ageing effects of kinetin were achieved without any increase in the cell culture lifespan in terms of maximum proliferative capacity in vitro. Hipkiss (2001) has pointed out that kinetin and three other agents that delay senescence in cultured cells (aminoguanidine, N-t-butylhydroxylamine, and carnosine) all react with glycoxidized proteins and possess anti-oxidant activity, suggesting that pluripotency may be a necessary prerequisite for effective anti-ageing activity.

Long-Lived Fruitflies

The median lifespan of the fruitfly Zaprionus paravittiger is 35 d, and even the most elderly do not live much more than 70 to 75 d. Sharma et al. (1995) reported that low levels of kinetin added to the diet of the fruitflies raised the median lifespan of males to 40 d, and the median lifespan of females to 63 d. The age of the most elderly males flies climbed from 70 to 79 d, and the most elderly females from 76 to 91 d. Higher concentrations of kinetin were toxic. Kinetin also slowed the developmental process: control larvae took 277 h to reach maturity, whereas kinetin-treated larvae took 327 h. The anti-ageing effects of kinetin, however, were not due primarily to this slowing-down of development, but rather to a reduction in the age-specific death rates throughout the adult lifespan. In a subsequent study, Sharma et al. (1997) reported that the egg laying capacity of kinetinfed fruitflies was reduced drastically as compared with those kept on a normal diet. These results support the view that improved maintenance of the soma and prolongation of its life is achieved at the cost of decreased re-productive activity.

Kinetin Helps Prevent Blood Clots

Kinetin is known to have anti-oxidative properties in plants, such as preventing the oxidation of unsaturated fatty acids in membranes (Leshem, 1988). Since intravascular thrombosis is believed to involve platelet adherence and aggregation, and since the activation of platelets leads to the production of free radicals in platelets, Hsiao et al. (2003) examined whether kinetin had an inhibitory activity on free radical formation in activated platelets in vitro and on thrombus formation in vivo. Kinetin (70 and 150 μm) reduced the electron spin resonance (ESR) signal intensity of hydroxyl radicals in collagen-activated platelets, and was effective in reducing the mortality of ADP-induced acute pulmonary thromboembolism in mice (Mus musculus) when administered intravenously. Intravenous injection of kinetin significantly prolonged the bleeding time by approximately twofold as compared with normal saline in severed mesenteric arteries of rats (Rattus norvegicus). A continuous infusion of kinetin (0.6 mg/kg/min) for 10 min also significantly increased the bleeding time by about 2.3-fold, and the bleeding time returned to baseline within 120 min after cessation of kinetin infusion. Platelet thrombi formation was induced by irradiation of mesenteric venules with filtered light in mice pre-treated intravenously with fluorescein sodium. When kinetin was administered at 13 and 14 mg/kg in mice pre-treated with fluorescein sodium (5 mg/kg), the occlusion time was significantly prolonged. These results suggest that kinetin has effective free radical-scavenging activity in vitro and antithrombotic activity in vivo. Treatment with kinetin may lower the risk of thromboembolic-related disorders. Therefore, kinetin may be a potential therapeutic agent for arterial thrombosis, but its toxicity must be further assessed.

Kinetin and Cancer

Acute myeloid leukemia cells do not undergo the differentiation that normally leads to functional blood cells. Instead, they are arrested at immature stages of development. Ishii et al. (2002) examined the effects of various adenine analogues on the growth and differentiation of human myeloid leukemia HL-60 cells. Kinetin, as well as isopentenyladenine and benzyladenine were very effective in inducing morphological changes in the cells into mature granulocytes. On the other hand, cytokinin ribosides such as kinetin riboside, isopentenyladenosine, and benzylaminopurine riboside were the most potent for growth inhibition and apoptosis. These results suggest that both cytokinins and cytokinin ribosides can induce granulocytic differentiation of HL-60 cells, but cytokinin ribosides also induce apoptosis prior to the differentiation process.