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Purpose: Advanced age is associated with an accumulation of free radical damage, which leads to physiological and clinical modifications. Numerous pharmaceutical and nutraceuticals are considered to influence longevity and prompting healthy ageing. Therefore, the current study attempted to investigate Curcumin's role in the inflammatory indices as anti-ageing marker in albino Wistar rats. Methods: Twelve months old rats were used in the study, grouped as Normal control (NC), Sham control (SC), Curcumin-1, Curcumin-2 and Curcumin-3. Last three groups received Curcumin at the dosages of 100 mg, 200 mg and 400 mg/kg body weight respectively. After six months of intervention, blood was collected for the estimation of C-reactive protein (CRP), Serum Albumin, Globulin, Lymphocyte percentage, Total Antioxidant Capacity (TAC), Malondialdehyde (MDA), Superoxide Dismutase (SOD) and Nitric Oxide (NO) level using standard procedures. Results: There was a significant decline in the CRP level (p < 0.05) in rats treated with 200 mg and 400 mg of Curcumin/kg body weight. The MDA level was found to be significantly increased (p < 0.05) in animals fed with 400 mg of Curcumin/kg body weight as compared to NC. The NO level was increased significantly (p < 0.05) in rats treated with 200 and 400 mg of Curcumin/kg body weight. Conclusion: Finding of the study suggests that Curcumin exhibits favorable influence in slowing down of ageing process by suppressing age-related changes in inflammatory indices.
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ORIGINAL ARTICLE
Anti-aging Role of Curcumin by Modulating
the Inammatory Markers in Albino Wistar Rats
Moodithaya Shailaja, Ph.D., K. M. Damodara Gowda, Ph.D., Kedilaya Vishakh, M.Sc.,
N. Suchetha Kumari, Ph.D.
Acknowledgement: Authors kindly acknowledge the nancial support given by
Nitte University.
Abstract: Purpose: Advanced age is associated with an accumulation of free
radical damage, which leads to physiological and clinical modications.
Numerous pharmaceutical and nutraceuticals are considered to inuence
longevity and prompting healthy ageing. Therefore, the current study
attempted to investigate Curcumins role in the inammatory indices as anti-
ageing marker in albino Wistar rats.
Methods: Twelve months old rats were used in the study, grouped as Normal
control (NC), Sham control (SC), Curcumin-1, Curcumin-2 and Curcumin-3. Last
three groups received Curcumin at the dosages of 100 mg, 200 mg and 400 mg/
kg body weight respectively. After six months of intervention, blood was
collected for the estimation of C-reactive protein (CRP), Serum Albumin,
Globulin, Lymphocyte percentage, Total Antioxidant Capacity (TAC),
Malondialdehyde (MDA), Superoxide Dismutase (SOD) and Nitric Oxide (NO)
level using standard procedures.
Results: There was a signicant decline in the CRP level (p <0.05) in rats treated
with 200 mg and 400 mg of Curcumin/kg body weight. The MDA level was found
to be signicantly increased (p <0.05) in animals fed with 400 mg of Curcumin/
kg body weight as compared to NC. The NO level was increased signicantly
(p <0.05) in rats treated with 200 and 400 mg of Curcumin/kg body weight.
Conclusion: Finding of the study suggests that Curcumin exhibits favorable
inuence in slowing down of ageing process by suppressing age-related
changes in inammatory indices.
Keywords: Curcumin-Anti-aging-C-reactive protein-Total antioxidant
capacity-Malondialdehyde-Superoxide dismutase-Nitric Oxide
Author afliations: Moodithaya Shailaja, Department of Physiology, K.S. Hegde Medical
Academy, Nitte University, Mangalore, India; K.M. Damodara Gowda, Department of
Physiology, K.S. Hegde Medical Academy, Nitte University, Mangalore, India; Kedilaya
Vishakh, Central Research Laboratory, K.S. Hegde Medical Academy, Nitte University,
Mangalore, India; N. Suchetha Kumari, Department of Biochemistry, K.S. Hegde Medical
Academy, Nitte University, Mangalore, India
Correspondence: K.M. Damodara Gowda, Ph.D., Department of Physiology, K.S. Hegde
Medical Academy, Nitte University, Mangalore 575018, India., email: dr_damodar@nitte.
edu.in
ª2017 by the National Medical Association. Published by Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jnma.2017.01.005
INTRODUCTION
Biological ageing not only limits individuals life-
span but also is a major risk factor for a range of
pathological conditions with signicant morbidity
and mortality. The ageing process as opposed to longevity
is a phenotypic event like any other disease which is
inuenced by genetic and environmental factors; in-
terventions in genetic and nutritional factors were found to
extend longevity.
1
Lifespan is regulated by genes
controlling the activity of metabolism, antioxidant system,
DNA repair, cellular senescence and cell death. However,
diverse tissues building organs may show different pat-
terns of senescence. To determine individuals/animals
biological age and to assess the effects of different anti-
ageing factors, biomarkers of ageing could be used. In
general, seven major health areas are affected by ageing.
These include cardiovascular health, glucose regulation,
brain function, musculoskeletal health, endocrine function,
immune system and oxidative stress.
2
Numerous pharmaceutical and nutraceuticals are
considered to inuence longevity and prompting healthy
ageing. Nutraceuticals are food ingredients which either
have proven physiological benets or provide protection
against chronic disease. They may contribute to the pre-
vention of diseases and ageing. Diet has a major role in
modulating the risk of development of several diseases and
successful ageing. Edible plants as dietary constituents are
important in that they contain phytochemicals which can
control biochemical process at cellular level of an animal
or individual.
Among nutraceuticals, the role of Curcumin is
supported by scientic evidence that conrm its anti-
inammatory and anti-oxidant action. Curcumin is a
phytochemical derived from the rhizome of Curcuma
longa, commonly known as turmeric gives Indian curry its
characteristic yellow color. It has been used as wound-
healing agent and for treating variety of diseases in tradi-
tional Indian and Chinese medicine. Recently, as cell death
inducer Curcumin has gained profound interest as an anti-
cancer agent which found conrmation in many in-vitro
and preclinical study on animal models. Further Curcu-
min is also used in the therapy of many diseases with an
inammation as component and includes cardiovascular,
Alzheimers diseases, rheumatoid arthritis and metabolic
diseases.
3,4
Proven benets of Curcumin, including prevention of
cancer, Alzheimers diseases, arthritis and cardiac diseases,
could translate its effect into longer lifespan. However,
comprehensive studies on anti-ageing effects of Curcumin
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL 109, NO 1, SPRING 2017 9
are lacking. Therefore the current study attempts to
investigate Curcumins role in the inammatory indices as
anti-ageing marker in albino Wistar rats.
MATERIALS AND METHODS
Experimental animal and study groups
A total of 40 adult female wistar albino rats of 2 months
old, weighing about 150e180 gm were used. The animals
were maintained under controlled conditions of tempera-
ture and light in an animal house of the institute and were
fed with standard rat feed and water till they are 12 months
old. All the experiments were performed in accordance
with the guidelines of institutional Animal Ethics Com-
mittee and the National Institutes of Health guide for the
care and use of Laboratory animals.
Twelve months old experimental animals were divided
into ve groups of eight rats each. They are Normal con-
trol (NC), Sham control (SC), Curcumin-1, Curcumin-2
and Curcumin-3. Normal control rats were fed with stan-
dard rat feed and water ad libitum. Sham control group
received distilled water along with standard rat feed and
water ad libitum. The Curcumin-1, Curcumin-2 and
Curcumin-3 received Curcumin at the dosages of 100 mg,
200 mg and 400 mg/kg body weight respectively. It was
administrated orally, daily for six months in addition to
standard rat feed and water. After six months of inter-
vention, the 18 months old animals were sacriced, blood
was collected by cardiac puncture and following in-
vestigations were carried out.
To assess the effect on ageing, inammatory markers
such as the level of C-reactive protein (CRP), Serum Al-
bumin, Serum Globulin, Albumin Globulin ratio (A:G
ratio), Lymphocyte percentage was measured using stan-
dard techniques. The CRP level was estimated by ELISA
method. The concentration of serum Albumin, Globulin,
A:G ratio was estimated using commercially available kits
and all the experiments were performed according to the
manufacturers guidelines. The lymphocyte percentage
was recorded using animal blood cell counter.
Estimation of lipid peroxidation
Markers of lipid peroxidation, called thiobarbituric acid-
reactive substances (TBARS), were measured in plasma
using a uorometric technique. Malondialdehyde, a sec-
ondary product of lipid peroxidation, reacts with thio-
barbituric acid (TBA) in the presence of acidic medium to
give a pink color pigment at 97 CatpHof2e3. The pink
color was extracted with butanol and the absorbance read
at 532 nm.
Estimation of total antioxidant capacity
(TAC)
Serum total antioxidant capacity was assessed using the
spectrophotometric method, the Trolox equivalent anti-
oxidant capacityassay.
Estimation of superoxide dismutase (SOD)
The principle of SOD activity assay was based on the
inhibition of nitroblue tetrazolium (NBT) reduction. The
reduction of NBT by superoxide radicals to blue coloured
formazan was followed at 565 nm. This was followed by
the inhibition of CuZnSOD with KCN and subsequent
measurements of the remaining enzymatic activity, which
was attributed to MnSOD.
Estimation of Nitric Oxide (NO)
Nitric Oxide measurement was done by Griess reagent
consisting of 1-naphthylyl ethylenediamine HCl and sul-
fanilamide is taken as a reection of NO generation.
Statistical analysis
The data was expressed as mean ±SD. The means of
various parameters of control and treated animals were
compared using ANOVA & Tukeys post-Hoc test for
statistical signicance. Null hypothesis was rejected for
P<0.05.
RESULTS
The C-reactive protein level in animals treated with
200 mg and 400 mg Curcumin/kg body weight was found
to be declined signicantly (p <0.05). But, there was no
signicant change in Sham control and rats treated with
Figure 1. Comparison of C-reactive protein level in different groups of
experimental animals. NC eNormal control, SC eSham control,
Curcumin-1, Curcumin-2 and Curcumin-3 are animals treated with
100 mg, 200 mg and 400 mg of curcumin/kg body weight respectively.
NS indicates Nonsignicant, * indicates p <0.05.
0
0.5
1
1.5
2
2.5
NC SC Curcumin-1 Curcumin-2 Curcumin-3
Experimental groups
C- reactive protein (mg/L)
NC vs SC and Curcumin-1, p>0.05 respectively
NC vs Curcumin-2 and 3, p<0.05 respectively
NS
NS
*
ANTI-AGING ROLE OF CURCUMIN
10 VOL. 109, NO 1, SPRING 2017 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
100 mg of Curcumin/kg body weight as compared to
normal control rats (Fig. 1). The total protein, serum al-
bumin, serum globulin and A:G ratio was not shown any
signicant variation in different experimental animals
when compared to control animals (Table 1). The change
in the percentage of lymphocytes on comparison with
animals of different experimental group was also found to
be insignicant (p >0.05, Fig. 2).
The multiple comparison of total antioxidant capacity
between the different groups showed no signicant change
(p >0.05). This indicated that TAC in CR animals was
maintained on treatment with Curcumin although the rats
were older (Fig. 3). On comparison of MDA level of normal
rats with that of rats treated with 400 mg of Curcumin/kg
body weight, which was signicantly higher (p <0.05,
Fig. 4). Whereas, in Sham control, Curcumin-1 and
Curcumin-2 rats the increase was found to be insignicant.
The superoxide dismutase (SOD) and Nitric Oxide ac-
tivity in all the experimental animals on comparison with
normal control rats did not exhibited signicant variation
from normal animals (p >0.05, Figs. 5 and 6
respectively).
DISCUSSION
Intervention aimed to slowing down ageing could provide
a greater benet than those targeted at individual disease.
Very few data is available to show that neutraceuticals may
alter the process of ageing by modulating inammation
constituents. The current study attempted to evaluate the
role of curcumin, a poly phenol derived herbal remedy and
the dietary spice on the inammatory indices of anti-
ageing marker in albino Wistar rats.
Table 1. Concentration of total protein, serum albumin, serum globulin and A:G ratio in different groups of experimental animals.
Mean ±SD
NC SC Curcumin-1 Curcumin-2 Curcumin-3
Total protein (g/dl) 9.58 ±3.45 9.03 ±1.82
(p ¼0.73,NS)
8.31 ±0.81
(p ¼0.40,NS)
9.35 ±1.59
(p ¼0.88,NS)
7.51 ±1.77
(p ¼0.22,NS)
Serum albumin (g/dl) 4.59 ±0.67 5.26 ±0.96
(p ¼0.19,NS)
5.06 ±0.64
(p ¼0.24,NS)
5.11 ±1.47
(p ¼0.44,NS)
4.42 ±1.55
(p ¼0.81,NS)
Serum globulin (g/dl) 4.97 ±3.35 3.79 ±1.04
(p ¼0.42,NS)
3.25 ±1.21
(p ¼0.26,NS)
4.24 ±2.78
(p ¼0.68,NS)
3.08 ±1.23
(p ¼0.22,NS)
A:G ratio 1.6 1.4
(p ¼0.67,NS)
1.6
(p ¼1.0,NS)
1.12
(p ¼0.32,NS)
1.4
(p ¼0.67,NS)
Note: NC eNormal control, SC eSham control, Curcumin-1, Curcumin-2 and Curcumin-3 are animals treated with 100 mg, 200 mg and
400 mg of curcumin/kg body weight respectively. NS indicates Nonsignicant.
Figure 2. Comparison of percentage of lymphocytes in different groups
of experimental animals. NC eNormal control, SC eSham Control,
Curcumin-1, Curcumin-2 and Curcumin-3 are animals treated with
100 mg, 200 mg and 400 mg of curcumin/kg body weight respectively.
NS indicates nonsignicant.
0
20
40
60
80
100
120
NC SC Curcumin-1 Curcumin-2 Curcumin-3
Experimental Groups
Lymphocyte%
NC vs SC, Curcumin-1, 2 and 3, p>0.05 respectively
NS
NS NS NS
Figure 3. Comparison of total antioxidant capacity between different
experimental animals. NC eNormal control, SC eSham control,
Curcumin-1, Curcumin-2 and Curcumin-3 are animals treated with
100 mg, 200 mg and 400 mg of curcumin/kg body weight respectively.
NS indicates nonsignicant.
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
NC SC Curcumin-1 Curcumin-2 Curcumin-3
Experimental Groups
TAC in mM/L
NC vs SC, Curcumin-1, 2 and 3, p>0.05 respectively
NS
NS
NS
ANTI-AGING ROLE OF CURCUMIN
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL 109, NO 1, SPRING 2017 11
Advanced age is associated with an accumulation of free
radical damage, which leads to physiological and clinical
modications. Age related changes resulting from free
radical reactions include increasing levels of lipid perox-
ides, alterations in enzyme activities. Many studies have
addressed the question of supplementation with antioxidant
vitamins, especially vitamins C and E, and synthetic com-
pounds can prolong the lifespan of model animals.
5
Finding of this study showed that, there is signicant
reduction in levels of CRP an anti-ageing inammatory
marker, in curcumin treated animals compared to that of
controls. Similarly results of analysis also showed that
curcumin treated animals exhibited signicant favorable
inuence on A:G ratio. Role of inammation in the pro-
cess of age related diseases is well established. Oxidative
damage with ageing, which further involves an inam-
matory response, may be one of the mechanisms leading to
elevation of inammatory markers during ageing process.
The results of the present study also showed the
effective modulation of antioxidants produced in ageing
animals on supplementation of different dosages of Cur-
cumin. This was shown by maintaining the total antioxi-
dant capacity, SOD activity in older animals treated with
Curcumin as same as in young rats. These antioxidant
enzymes serve as the bodys most potent defense against
free radicals and ensuing inammatory reactions and by
facilitating reactions that render toxins less harmful.
The signicant increase in the NO level in the aged
experimental animals shown in the present study clearly
explains the antiaging effect of curcumin in the experi-
mental animals. As age advances, the bodys ability to
produce benecial levels of Nitric Oxide decreases leading
to stiffening and narrowing of arteries, intern leading to a
number of serious health concerns including elevated
blood pressure, heart disease, stroke, chronic inammation
and decreased sexual function.
6e8
Findings of this leads to
scope for further research to explore the underlying
mechanism for benecial effect of this neutracuetical
substance, that would provide deeper insight in under-
standing of curcumin as a potential therapeutic agent.
The data of the present study demonstrates that the
intervention with curcumin, an active compound in edible
turmeric is associated with an altered prole of anti-ageing
inammatory markers as assessed by levels of CRP. The
anti-ageing property of curcumin could be due to its well
established antioxidant and anti-inammatory properties
that control the biochemical process at cellular level.
Further investigation is required to document anti ageing
property of curcumin by assessing appropriate dosage and
also using more sensitive ageing biomarkers.
IMPLICATION
The ndings of this study explored the anti-ageing inu-
ence of curcumin in wistar rats provide the opportunity for
Figure 5. Comparison of superoxide dismutase activity in different
experimental animals. NC eNormal control, SC eSham control,
Curcumin-1, Curcumin-2 and Curcumin-3 are animals treated with
100 mg, 200 mg and 400 mg of curcumin/kg body weight respectively.
NS indicates nonsignicant.
0
5
10
15
20
25
30
NC SC Curcumin-1 Curcumin-2 Curcumin-3
SOD activity in U/g protein
Experimental groups
NC vs SC, CR, Group IV, V and VI, p>0.05 respectively
Figure 6. Comparison of Nitric Oxide level in different experimental
animals. NC eNormal control, SC eSham control, Curcumin-1,
Curcumin-2 and Curcumin-3 are animals treated with 100 mg, 200 mg
and 400 mg of curcumin/kg body weight respectively. NS indicates
nonsignicant, * indicates p <0.05.
0
2
4
6
8
10
12
14
NC SC Curcumin-1 Curcumin-2 Curcumin-3
NO in μM/L
Experimental groups
NC vs SC and Curcumin-1, p>0.05
NC vs Curcumin-2 and 3, p<0.05 respectively
Figure 4. Comparison of MDA level in different experimental animals.
NC eNormal control, SC eSham control, Curcumin-1, Curcumin-2 and
Curcumin-3 are animals treated with 100 mg, 200 mg and 400 mg of
curcumin/kg body weight respectively. NS indicates nonsignicant, *
indicates p <0.05.
0
0.5
1
1.5
2
2.5
3
3.5
NC SC Curcumin-1 Curcumin-2 Curcumin-3
MDA in μM/L
Experimental Groups
NC vs SC, Curcumin-1 and 2, p>0.05 respectively
*NC vs Curcumin-3, p<0.05.
NS
ANTI-AGING ROLE OF CURCUMIN
12 VOL. 109, NO 1, SPRING 2017 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
evaluation of benets of curcumin in human population
using longitudinal study. There is increased demand for
healthy longevity, and understanding the anti ageing effect
of a functional food would be of potential benet espe-
cially for the individuals with diseases associated with
accelerated ageing. Understanding anti-ageing effect of
Curcuma longa could bring novel perspectives in nding
adjunctive therapy for the different types of age-related
diseases.
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JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL 109, NO 1, SPRING 2017 13
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Aim Aging can origin changes in the heart that may increase risk of developing cardiovascular disease. This study aimed to characterize autophagy alterations and related molecular mediators in the heart tissue in the aging alone or in combination with exercise and curcumin treatment. Methods Seven young and twenty-eight elderly male Wistar rats were assigned into five groups, namely: young control, age, exercise, curcumin, and curcumin+exercise. Aged rats in exercise group run on treadmill (17 m/min) and in the curcumin group received curcumin (50 mg/kg) by gavage daily for 8 weeks for 2 months. At the end, heart samples were collected and used for determination of autophagy by immunostaining for LC3-phosphatidylethanolamine conjugate (LC3-II), apoptosis by TUNEL assay, Malondialdehyde (MDA) level by enzymatic assay and determination of mediators' molecules by ELISA for NADPH Oxidase 4 (NOX4), sirtuin 1 (SIRT-1), phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells (p-NF-Ƙb) protein levels and Sequestosome-1 (P62). Also, histological changes such as fibrosis evaluated by Masson trichrome staining. Results Our results showed that autophagy, SIRT-1 level were significantly decreased and MDA, NOX4, p-NF-Ƙb and P62 levels were significantly increased in heart of aged group compared to young group. Also, significant increased apoptosis and fibrosis levels in the heart of aged rats were observed compared with young rats, whereas, these undesirable changes were improved by exercise and curcumin. Also, combination therapy of aged rats with curcumin and exercise showed more significant prominent effect on molecular mediators and histological changes in the heart compared with monotherapy. Conclusion These findings indicate that stress oxidative increase and autophagy decrease in the heart tissue of aged rats. The age induced the mentioned changes in the heart may in part be associated with down-expression of SIRT-1 and overexpression of NOX4 proteins. It was also showed that these age induced effects can be alleviated by treatment with exercise and curcumin. Since NF-Ƙb increased in both the age and treatment groups, it seems the age heart increased NF-Ƙb to be due to a compensatory mechanism.
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Background: The `fetal origins' hypothesis proposes that alterations in fetal nutrition result in a permanent change in physiology and metabolism, thereby predisposing to metabolic disorders in adult life. Turmeric (Curcuma longa L.), the wonder queen of Indian spice and a nutraceutical was extensively used in Ayurveda, Unani, and Siddha for various diseases. Having multiple benefits of Curcumin, we hypothesized that, rats suffered undernutrition during their perinatal period would develop metabolic disorders in their adult life, which would be effectively modulated by Curcumin. Therefore, the present study was designed to investigate the effect of Curcumin supplementation during perinatal life. Methods: It is an experimental study conducted using a rat model. The animals were divided into six groups. The insulin level was estimated by the enzyme-linked immunosorbent assay (ELISA) method. Plasma glucose and lipid profile by autoanalyzer method. HOMA-IR and AI were calculated. The difference was compared between the groups and within the group was done by one-way ANOVA. The p < 0.05 was considered as the level of significance. Results: The Bodyweight mean Triglyceride, Total cholesterol, LDL-C, Glucose, AI, and HOMA-IR was significantly increased (p=0.0001) in the Perun group, whereas HDL-C and Insulin were significantly decreased (p=0.001) as compared to control animals, which was effectively modulated by Curcumin in the animals of PeriCur group. Conclusion: The present study showed that perinatal undernutrition caused metabolic disorders in adult life and was effectively modulated by Curcumin supplementation during the perinatal period.
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Dementia is a chronic condition characterized by the decreased cognitive capacity, which is more severe than in case of normal aging. Cognitive impairment is a major social and economic problem of modern society, which affects about 47 million people worldwide. The first stage of dementia (mild cognitive impairment) is characterized by the decline of memory, executive function, attention, visuospatial skills and speech. Pathogenic links of cognitive impairment are represented by neuroinflammation, excessive amyloid-β protein deposition, oxidative stress, hyperphosphorylation etc. In the recent years, the interest in natural plant-derived compounds for the treatment of cognitive decline has increased. In this chapter, we summarize the available evidence supporting the benevolent action of some botanicals and phytochemicals on cognitive function. The most widely studied plants include Ginkgo biloba, Panax ginseng and Camellia sinensis (green tea), but there also some other promising ones like guarana, grape, soy etc. These nutraceuticals mostly influence memory, learning and attention. At the moment it is quite difficult to make a definite conclusion on the effects of nutraceuticals on cognitive decline, because human trials show significant discrepancies. This underpins the need of future trials and scientific analysis.
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Nutraceuticals are considered as a safe alternative to allopathic medicine and therefore are widely used for wound healing as well as part of antiaging cosmetics. In this chapter, we describe the anatomy and physiology of skin followed by the current understanding of the wound healing process. Finally, we describe some well-known nutraceuticals that have shown wound healing potential and antiaging properties on the skin. As skin nutraceuticals are an upcoming market, knowledge about phytoconstituents, their mechanisms of action, and therapeutic uses are essential.
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A Symposium regarding the Pathophysiology of Successful and Unsuccessful Ageing was held in Palermo, Italy between April 7 and 8th 2009. Here the lecture by Sikora with some input from the chairpersons Scapagnini and Barbagallo is summarized. Ageing is manifested by the decreasing health status and increasing probability to acquire age-related disease such as cancer, Alzheimer's disease, atherosclerosis, metabolic disorders and others. They are likely caused by low grade inflammation driven by oxygen stress and manifested by the increased level of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-alpha, encoded by genes activated by the transcription factor NF-kappaB. It is believed that ageing is plastic and can be slowed down by caloric restriction as well as by some nutraceuticals. Accordingly, slowing down ageing and postponing the onset of age-related diseases might be achieved by blocking the NF-kappaB-dependent inflammation. In this review we consider the possibility of the spice curcumin, a powerful antioxidant and anti-inflammatory agent possibly capable of improving the health status of the elderly.
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Accumulation of oxidatively altered cell components may play a role in the age-related cell deterioration and associated diseases. Caloric restriction is the most robust anti-aging intervention that extends lifespan and retards the appearance of age-associated diseases. Autophagy is a highly conserved cell-repair process in which the cytoplasm, including excess or aberrant organelles, is sequestered into double-membrane vesicles and delivered to the degradative vacuoles. Autophagy has an essential role in adaptation to fasting and changing environmental conditions. Several pieces of evidence show that autophagy may be an essential part in the anti-aging mechanism of caloric restriction: 1. The function of autophagy declines with increasing age; 2. The temporal pattern of the decline parallels the changes in biomarkers of membrane aging and in amino acid and hormone signalling. 3. These age-dependent changes in autophagy are prevented by calorie restriction. 4. The prevention of the changes in autophagy and biomarkers of aging co-varies with the effects of calorie restriction on life-span. 5. A long-lasting inhibition of autophagy accelerates the process of aging. 6. A long-lasting stimulation of autophagy retards the process of aging in rats. 7. Stimulation of autophagy may rescue older cells from accumulation of altered mtDNA. 8. Stimulation of autophagy counteracts the age-related hypercholesterolemia in rodents. It is suggested that the pharmacological intensification of suppression of aging (P.I.S.A. treatment) by the stimulation of autophagy might prove to be a big step towards retardation of aging and prevention of age-associated diseases in humans.
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Chronic dietary restriction (DR) is considered among the most robust life-extending interventions, but several reports indicate that DR does not always extend and may even shorten lifespan in some genotypes. An unbiased genetic screen of the lifespan response to DR has been lacking. Here, we measured the effect of one commonly used level of DR (40% reduction in food intake) on mean lifespan of virgin males and females in 41 recombinant inbred strains of mice. Mean strain-specific lifespan varied two to threefold under ad libitum (AL) feeding and 6- to 10-fold under DR, in males and females respectively. Notably, DR shortened lifespan in more strains than those in which it lengthened life. Food intake and female fertility varied markedly among strains under AL feeding, but neither predicted DR survival: therefore, strains in which DR shortened lifespan did not have low food intake or poor reproductive potential. Finally, strain-specific lifespans under DR and AL feeding were not correlated, indicating that the genetic determinants of lifespan under these two conditions differ. These results demonstrate that the lifespan response to a single level of DR exhibits wide variation amenable to genetic analysis. They also show that DR can shorten lifespan in inbred mice. Although strains with shortened lifespan under 40% DR may not respond negatively under less stringent DR, the results raise the possibility that life extension by DR may not be universal.
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Aging at the molecular level is characterized by the progressive accumulation of molecular damage. The sources of damage act randomly through environmental and metabolically generated free radicals, through spontaneous errors in biochemical reactions, and through nutritional components. However, damage to a macromolecule may depend on its structure, localization and interactions with other macromolecules. Damage to the maintenance and repair pathways comprising homeodynamic machinery leads to age-related failure of homeodynamics, increased molecular heterogeneity, altered cellular functioning, reduced stress tolerance, diseases and ultimate death. Novel approaches for testing and developing effective means of intervention, prevention and modulation of aging involve means to minimize the occurrence and accumulation of molecular damage. Mild stress-induced hormesis by physical, biological and nutritional methods, including hormetins, represents a promising strategy for achieving healthy aging and for preventing age-related diseases.
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The evolutionary theory of ageing explains why ageing occurs, giving valuable insight into the mechanisms underlying the complex cellular and molecular changes that contribute to senescence. Such understanding also helps to clarify how the genome shapes the ageing process, thereby aiding the study of the genetic factors that influence longevity and age-associated diseases.
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The size and frequency of meals are fundamental aspects of nutrition that can have profound effects on the health and longevity of laboratory animals. In humans, excessive energy intake is associated with increased incidence of cardiovascular disease, diabetes, and certain cancers and is a major cause of disability and death in industrialized countries. On the other hand, the influence of meal frequency on human health and longevity is unclear. Both caloric (energy) restriction (CR) and reduced meal frequency/intermittent fasting can suppress the development of various diseases and can increase life span in rodents by mechanisms involving reduced oxidative damage and increased stress resistance. Many of the beneficial effects of CR and fasting appear to be mediated by the nervous system. For example, intermittent fasting results in increased production of brain-derived neurotrophic factor (BDNF), which increases the resistance of neurons in the brain to dysfunction and degeneration in animal models of neurodegenerative disorders; BDNF signaling may also mediate beneficial effects of intermittent fasting on glucose regulation and cardiovascular function. A better understanding of the neurobiological mechanisms by which meal size and frequency affect human health may lead to novel approaches for disease prevention and treatment.
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Neurodegenerative diseases result in the loss of functional neurons and synapses. Although future stem cell therapies offer some hope, current treatments for most of these diseases are less than adequate and ourbest hope is to prevent these devastating diseases. Neuroprotective approaches work best prior to the initiation of damage, suggesting that some safe and effective prophylaxis would be highly desirable. Curcumin has an outstanding safety profile and a number of pleiotropic actions with potential for neuroprotective efficacy, including anti-inflammatory, antioxidant, and anti-protein-aggregate activities. These can be achieved at submicromolar levels. Curcumin's dose-response curves are strongly dose dependent and often biphasic so that in vitro data need to be cautiously interpreted; many effects might not be achievable in target tissues in vivo with oral dosing. However, despite concerns about poor oral bioavailability, curcumin has at least 10 known neuroprotective actions and many of these might be realized in vivo. Indeed, accumulating cell culture and animal model data show that dietary curcumin is a strong candidate for use in the prevention or treatment of major disabling age-related neurodegenerative diseases like Alzheimer's, Parkinson's, and stroke. Promising results have already led to ongoing pilot clinical trials.
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Aging denotes a postmaturational deterioration of cells and organisms with the passage of time, an increased vulnerability to challenges and prevalence of age-associated diseases, and a decreased ability to survive. Causes of this deterioration may be found in an enhanced production of reactive oxygen species (ROS) and oxidative damage and incomplete "housekeeping." Caloric restriction is the most robust anti-aging intervention known so far. Similar beneficial effects on median and maximum life span were obtained by feeding animals a 40%-reduced diet or by every-other-day ad libitum feeding. In both instances, animals are forced to spend a great part of their time in a state of fasting and activated autophagy. Autophagy is a highly conserved process in eukaryotes, in which the cytoplasm, including excess or aberrant organelles, is sequestered into double-membrane vesicles and delivered to the lysosome/vacuole, for breakdown and eventual recycling of the resulting macromolecules. This process has an essential role in adaptation to fasting and changing environmental conditions, cellular remodeling during development, and accumulation of altered ROS-hypergenerating organelles in older cells. Several pieces of evidence show that autophagy is involved in aging and is an essential part of the anti-aging mechanism of caloric restriction. As an application, intensification of autophagy by the administration of an antilipolytic drug rescued older cells from accumulation of altered mtDNA in less than 6 hours. It is concluded that the pharmacologic intensification of autophagy (PISA treatment) has anti-aging effects and might prove to be a big step toward retardation of aging and prevention of age-associated diseases in humans.