An introduction to the anti-aging molecule KINETIN
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Other
scientists have reported several other effects of kinetin, such as
anti-thrombotic effects, skin whitening effects, RNA missplicing
correction effects etc.
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Kinetin is now a component of
several skin care cosmetics and cosmeceuticals produced in several
countries all around the world. It has the potential to be developed into
various other health care products in the form of nutritional supplements,
eye wash anti-cataract agent, antithrombotic agent etc.
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More
recently, we have also reported the anti-aging effects of zeatin (another
cytokinin) on longe term cultures of human skin fibroblasts. See our paper:
Rattan, S.I.S. and Sodagam, L. Gerontomodulatory and
youth-preserving effects of zeatin on human skin fibroblasts undergoing
aging in vitro.
Rejuvenation Research, 8: 46-57,
2005.
Major producers of kinetin- and
zeatin-based skin care products are Valeant, Body Shop, Revlon, Ferrosan, and others.
For
further details on kinetin and other anti-aging cytokinins
etc, please contact
SENETEK PLC, who carry the rights
of use.
Patents -
Inventor: Rattan, S.I.S.
Title: Method and composition for ameliorating the adverse effects of
aging.
Patents
granted in several countries,
since 1994, including those in North and South America, Asia,
Europe etc.
Our publications on kinetin
15. Rattan, S.I.S. & Siboska, G. Kinetin: et potentielt
anti-aldringsmolekyle. Dansk Kemi, 82
(#11), 45-47, 2001. (in Danish)
14. Rattan, S.I.S. N6-furfuryladenine or kinetin as an
anti-aging molecule. Journal of
Anti-Aging Medicine, 4, 2002.
13. Barciszweski, J., Siboska, G., Rattan, S.I.S. &
Clark, B.F.C. Occurrence, biosynthesis and
properties of kinetin (N6-furfuryladenine). Plant Growth
Regulation, 32, 257-265, 2000.
12. Barciszweski, J., Siboska, G., Clark, B.F.C &
Rattan, S.I.S. Cytokinin formation by oxidative
metabolism. Journal of Plant Physiology, 157, 587-588,
2000.
11. Verbeke, P., Siboska, G.E., Clark, B.F.C. & Rattan,
S.I.S. Kinetin inhibits protein oxidation
and glycoxidation in vitro. Biochemical and Biophysical
Research Communications, 276,
1265-1270, 2000.
10. Olsen, A., Siboska, G.E., Clark, B.F.C. and Rattan,
S.I.S. N6-furfuryladenine, kinetin,
protects against Fenton reaction-mediated oxidative damage
to DNA. Biochemical and
Biophysical Research Communications, 265: 499-502, 1999.
9. Barciszewski, J., Barciszewska, M., Siboska, G.,
Rattan, S.I.S. and Clark, B.F.C. Some unusual
nucleic acid bases are products of hydroxyl radical
oxidation of DNA and RNA. Molecular
Biology Reports, 26, 31-38, 1999.
8. Barciszewski, J., Rattan, S.I.S., Siboska, G. and
Clark, B.F.C. Kinetin - 45 years on. Plant
Science, 148, 37-45, 1999.
7. Sharma, S.P., Kaur, J. and Rattan, S.I.S.Increased
longevity of kinetin-fed Zaprionus fruitflies
is accompanied by their reduced fecundity and enhanced
catalase activity. Biochemistry and
Molecular Biology International, 41, 869-875, 1997.
6. Barciszewski, J., Siboska, G.E., Pedersen, B.O.,
Clark, B.F.C. and Rattan, S.I.S. Furfural, a
precursor of the cytokinin hormone kinetin, and base
propenals are formed by hydroxy radical
damage of DNA. Biochemical and Biophysical Research
Communications, 238, 317-319, 1997.
5. Barciszewski, J., Siboska, G.E., Pedersen, B.O.,
Clark, B.F.C. and Rattan, S.I.S. A mechanism
for the in vivo formation of kinetin as a secondary
oxidative damage product in DNA. FEBS
Letters, 414, 457-460, 1997.
4. Barciszewski, J., Siboska, G.E., Pedersen, B.O.,
Clark, B.F.C. and Rattan, S.I.S. Evidence for
the presence of kinetin in DNA and cell extracts. FEBS
Letters, 393, 197-200, 1996.
3. Sharma, S.P., Kaur, P. and Rattan, S.I.S.Plant
growth hormone kinetin delays ageing, prolongs
the lifespan and slows down development of the fruitfly
Zaprionus paravittiger.Biochemical and
Biophysical Research Communications, 216, 1067-1071, 1995.
2. Rattan, S.I.S. and Clark, B.F.C. Kinetin delays the
onset of ageing characteristics in human
fibroblasts. Biochemical and Biophysical Research
Communications, 201, 665-672, 1994.
1. Barciszewski, J., Otzen, D., Rattan, S.I.S. and
Clark, B.F.C. Specific incorportation of kinetin
into eukaryotic and prokaryotic transfer ribonucleic acid
molecules. Biochemistry International, 28, 805-811, 1992.
A brief review of kinetin
(as per 2002)
The science behind kinetin as an
anti-aging molecule
Dr. Suresh I. S. Rattan
Laboratory of Cellular Aging, Danish Centre for Molecular Gerontology,
Department of Molecular Biology, University of Aarhus,
Denmark.
Historically, a wide variety of cosmetic formulations have been
created, sold and utilized for the treatment and/or prevention of
aging-related alterations, particularly the facial wrinkles. These
formulations ranged from plant and animal product-based concoctions in the
ancient times, to the use of serum growth factors, herbal extracts, and
human fetal and cellular extracts in recent times. Generally, there was
very little or no systematic scientific research performed to back up the
claims made for such formulations. However, during the last two decades,
this situation has been undergoing some change, and several new compounds
have been scientifically tested to varying extents. In such studies, a
compound is generally tested for its effects on the short-term growth and
survival of mammalian (including human) cells in culture. This is often
followed by its testing on animals for acute toxicity, and on a limited
number of human volunteers for determining its effects on gross facial
wrinkles commonly associated with sun exposure and photo-aging. Using this
strategy, some of the compounds which have been shown to have some effects
on reducing the photo-aging-related alterations in the skin include
alphahydroxy acid (AHA), glycolic acid, vitamin A (retinoic acid or
retinol), co-enzyme Q10, beta-alanyl-histidine dipeptide carnosine, and
N6-furfuryladenine or kinetin.
Kinetin is one of these compounds whose anti-aging effects on cultured
human skin cells were first reported by us. What follows is a brief
description and discussion of the chemical structure, biological effects,
modes of action, and potential areas of application of kinetin in health
care and anti-aging therapies.
Chemical properties and natural occurrence of kinetin
Kinetin was isolated for the first time in 1955 from autoclaved Herring
sperm DNA [1, 2]. It is a derivative of adenine which is one of the
nucleic acid purine bases, and belongs to the cytokinin group of plant
growth hormones. Kinetin is an amphoteric compound which is soluble in
strong acids, alkalis, and glacial acetic acid, is slightly soluble in
ethanol, butanol, acetone and ether, but is practically insoluble in
distilled water. Crystals of kinetin suitable for X-ray analysis have been
obtained by slow cooling of a hot ethanol solution. Identification of
kinetin in natural products was facilitated by our discovery of its
electrochemical properties. The crucial evidence for the presence of
N6-furfuryladenine in natural products came from our studies on the mass
spectrometric analysis of DNA components [3-5]. Using these methods,
kinetin has been reported to be present naturally in various plants [6,
7], and human cell extracts and DNA [3]. The biosynthetic pathway of
kinetin involves the formation of furfural during hydroxyl radical
oxidation of the deoxyribose in DNA, its reaction with the exocyclic amino
groups of adenine residues, followed by dehydration and reduction of the
intermediates leading to formation of N6-furfuryladenine [4, 5]. It is not
known if certain DNA repair enzymes then remove this modified base from
the DNA and make it available as free kinetin in the cell.
Biological properties
Data regarding the biological properties of kinetin are scattered
throughout literature, often in combination with studies on the effects of
other cytokinins. Most of the data for the biological properties of
kinetin come from studies on its effects on plant systems. Kinetin
stimulates tRNA synthesis, cell cycle progression and the catalytic
activity of the cyclin-dependent kinase (cdc2) in plant cells. Low levels
of kinetin stimulate calcium influx through the plasma-membrane calcium
channel in plant cells. Kinetin protects plant cells against stress by
suppressing cell death by viruses and toxic chemicals such as mercuric
chloride. Kinetin is well known for its anti-aging effects in plants. It
prevents yellowing and senescence of leaves, and slows down over-ripening
and degeneration of fruits (for a recent detailed review, see [8]).
We have reported strong anti-aging effects of kinetin on human skin cells
and fruitflies. We have shown that 40-80 micromolar (approximately 10?20
ppm) kinetin delays the onset of several cellular and biochemical
characteristics associated with cellular aging in long term cultures of
human skin fibroblasts [9]. Dermal fibroblasts continuously grown in
culture medium supplemented with kinetin did not undergo severe
morphological changes such as cell enlargement, vacuolization and
irregular flattened appearance. Kinetin-treated cells did not accumulate
debris associated with age-pigment lipofuscin and other oxidatively
modified macromolecules. Growth of human cells in kinetin-containing
medium also prevented the disorganization of the cytoskeleton and the
appearance of multinuclear cells during aging in vitro. Although kinetin
could slightly revert some of the age-related changes in senescent human
skin cells in vitro, its effects were most pronounced as a preventive
compound over a long-term treatment [9, 10]. Most importantly, treatment
of human cells with the above doses of kinetin neither caused premature
cell death (a sign of toxicity) nor did it induce extra cell proliferation
which is a sign of potential carcinogenesis. In this respect, kinetin
differs significantly from other so-called anti-aging compounds which can
either cause some cell death (for example, retinol) or can promote cell
proliferation (for example, serum growth factors and carnosine [11, 12]).
We have also tested the effects of kinetin in combination with glycolic
acid and retinol on the short-term growth, morphology and survival of
human skin fibroblasts (unpublished data available with Senetek PLC).
These results show that a combination of kinetin with these compounds have
no adverse effects on human cells. Rather, some preliminary data indicate
that kinetin may be able to neutralize some of the toxic effects of
retinol observed in human cell cultures. However, this needs to be
documented by further research.
In order to find out the effects of kinetin on the aging and lifespan of
organisms, we have performed studies using fruitflies. We have reported
that 25?50 ppm kinetin added to the food of fruitflies slowed down their
development and aging, and prolonged their average and maximum lifespan by
65% and 25%, respectively [13]. Furthermore, the increase in the lifespan
of kinetin-fed fruitflies was accompanied by a 55?60% increase in the
activity of an antioxidant enzyme catalase, which breaks down the toxic
compound hydrogen peroxide in the cells [14]. At present, there are no
studies performed on the effects of kinetin on aging, age-related
pathology and longevity of mammals.
In human trials for the cosmetic application of kinetin, double blind
vehicle-controlled 24?48 week studies of kinetin lotions (0.01?0.1%) have
been performed at the Department of Dermatology, University of California,
Irvine, USA. In this study comprising 64 human subjects, twice a day
topical application of kinetin on facial skin has shown consistent
clinical global improvement in several photo-aging-related markers. These
markers include fine wrinkles, coarse wrinkles, actinic lentigines,
mottled hyperpigmentation, telangiectasia, tactile skin roughness and
total water loss. The positive effects of kinetin observed on more than
95% of the test subjects were recorded without any associated negative
effects such as skin burning or stinging, erythema, peeling and dryness
(unpublished data available with Senetek PLC).
Mechanisms of action and future applications
Although the exact mechanisms of action of kinetin are yet to be
revealed, various lines of evidence indicate that kinetin is involved in
signal transduction and also acts as a natural antioxidant [8]. As a
signaling molecule, kinetin may stimulate other defense pathways, such as
DNA repair and proteosome-mediated protein turnover. In an analysis of the
antioxidative character of kinetin as a free radical scavenger one could
consider two possibilities: (1) oxygen radicals can directly abstract
hydrogen from the a-carbon of the amine bond of N6-furfuryladenine; or (2)
they can undergo faster dismutation reaction in aqueous solution when
kinetin is complexed with copper. A direct effect of kinetin on superoxide
dismutase activity has been observed in plants [8]. Our studies have shown
that kinetin protects DNA from hydrogen peroxide-induced formation of
mutagenic 8-oxodeoxyguanine (8-oxodG) by the Fenton reaction in vitro
[15]. Recently, we have observed that kinetin protects against oxidative
and glycoxidative protein damage generated in vitro by sugars and by an
iron/ascorbate system [16].
Considering that kinetin appears to be a powerful natural antioxidant
with pluripotent effects, its applications in health care and biomedicine
need to be investigated thoroughly. The effects of kinetin on the
prevention and treatment of those conditions occurring due to the damage
to DNA (for example, cancers), and to proteins and other macromolecules
resulting in the accumulation of abnormal proteins and lipids in various
organs, tissues and cells (for example, cataract, maculopathy, Alzheimer?s
disease and others) should be investigated. The usefulness of kinetin as a
nutritional supplement in stimulating the maintenance and repair pathways
in the body, and as a general molecule of defense and a component of the
homeodynamic machinery also need to be explored thoroughly.
References
1. Miller, C.O., Skoog, F., Von Saltza, M.H. and Strong, F.M. (1955):
Kinetin, a cell division factor from deoxyribonucleic acid. J. Amer. Chem.
Soc. 77, 1392.
2. Miller, C.O., Skoog, F., Okumura, F.S., Von Saltza, M.H. and Strong,
F.M. (1956): Isolation, structure and synthesis of kinetin, a substance
promoting cell division. J. Amer. Chem. Soc. 78, 1375-1380.
3. Barciszewski, J., Siboska, G.E., Pedersen, B.O., Clark, B.F.C. and
Rattan, S.I.S. (1996): Evidence for the presence of kinetin in DNA and
cell extracts. FEBS Lett. 393, 197-200.
4. Barciszewski, J., Siboska, G.E., Pedersen, B.O., Clark, B.F.C. and
Rattan, S.I.S. (1997): A mechanism for the in vivo formation of
N6-furfuryladenine, kinetin, as a seondary oxidative damage product in
DNA. FEBS Lett. 414, 457-460.
5. Barciszewski, J., Siboska, G.E., Pedersen, B.O., Clark, B.F.C. and
Rattan, S.I.S. (1997): Furfural, a precursor of the cytokinin hormone
kinetin, and base propenals are formed by hydroxyl radical damage of DNA.
Biochem. Biophys. Res. Commun. in 238, 317-319.
6. Raman, N. and Elumalai, S. (1996): Presence of cytokinin in the root
nodules of Casuarina equisetifolia. Ind. J. Exp. Biol. 34, 577-579.
7. Ratti, N. and Janardhanan, K.K. (1996): Effect on growth and cytokinin
contents of palmrosa (Cymbopogon martinii var. motia) by Glomus
inoculation. Ind. J. Exp. Biol. 34, 1126-1128.
8. Barciszewski, J., Rattan, S.I.S., Siboska, G. and Clark, B.F.C.
(1999): Kinetin - 45 years on. Plant Sci. 148, 37-45.
9. Rattan, S.I.S. and Clark, B.F.C. (1994): Kinetin delays the onset of
ageing characteristics in human fibroblasts. Biochem. Biophys. Res. Commun.
201, 665-672.
10. Rattan, S.I.S. (1994): Method and composition for ameliorating the
adverse effects of aging. United States Patent, No. 5,371,089.
11. McFarland, G.A. and Holliday, R. (1994): Retardation of the
senescence of cultured human diploid fibroblasts by carnosine. Exp. Cell
Res. 212, 167-175.
12. McFarland, G.A. and Holliday, R. (1999): Further evidence for the
rejuvenating effects of the dipeptide L-carnosine on cultured human
diploid fibroblasts. Exp. Gerontol. 34, 35-45.
13. Sharma, S.P., Kaur, P. and Rattan, S.I.S. (1995): Plant growth
hormone kinetin delays ageing, prolongs the lifespan and slows down
development of the fruitfly Zaprionus paravittiger. Biochem. Biophys. Res.
Commun. 216, 1067-1071.
14. Sharma, S.P., Kaur, J. and Rattan, S.I.S. (1997): Increased longevity
of kinetin-fed Zaprionus fruitflies is accompanied by their reduced
fecundity and enhanced catalase activity. Biochem. Mol. Biol. Int. 41,
869-875.
15. Olsen, A., Siboska, G.E., Clark, B.F.C. and Rattan, S.I.S. (1999):
N6-furfuryladenine, kinetin, protects against Fenton reaction-mediated
oxidative damage to DNA. Biochem. Biophys. Res. Commun. 265, 499-502.
16. Verbeke, P., Siboska, G.E., Clark, B.F.C. and Rattan, S.I.S. (2000):
Kinetin inhibits protein oxidation and glyoxidation in vitro. Biochem.
Biophys. Res. Commun. 276, 1265-1270, 2000.
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