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Medicinal Plants, Antioxidant Potential,

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andApplications toAging

AabirPramanik, SonaliMaheshwari, andNiyatiAcharya

Abstract

Aging is a progressive process in the body where wrinkling, ne lines of the skin, graying and thinning of hair, brittle and pale nails, and fragility in bones are obvious due to the breakdown of collagens, elastin, reduced production of melanin, and hormonal changes. DNA damage, telomerase shortening, alteration in specic genes, increase in the reactive oxygen species level, and mitochondrial dysfunction are the leading causes of aging. These internal factors are aggravated by some external factors like chronic sun exposure specically UVA and UVB, smoking, alcohol consumption, radiation, pollution, exposure to metal ions and toxic chemicals, and nutrient deciencies. To correct these signs of aging, antioxidants are widely used to treat and prevent the early signs of aging. Many medicinal plants, which have been used for thousands of years, are found in Rasayana category, a category of the Indian traditional health care system (Ayurveda) advocated for its intriguing antioxidant effects. Some of the medicinal plants utilized in Ayurveda as Rasayana for their therapeutic activity have been wellresearched for its antiaging properties. This chapter focuses on some important plant material and isolated compounds that are reported to have ability to slow down the rate of aging and used worldwide. Majority of them exhibited anti-aging effects through their antioxidants potential.

Keywords

Aging · Antioxidant · Anti-aging · Medicinal plants · Phytoconstituents

A. Pramanik · S. Maheshwari Institute of Pharmacy, Nirma University, Ahmedabad, India

N. Acharya (*) Department of Pharmacognosy, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India e-mail: niyati.acharya@nirmauni.ac.in

1 Introduction

Aging is a biological process that gradually inuences the normal processes in the cells and the tissues. Since the body is unable to generate new body cells during this phase, there is no elimination of dead or defective cells from multiple parts of the body [1]. Internal and environmental variables are thought to play signicant roles in the aging process. Internal factor involves normal biological processes of the cell. Environmental variables include ultraviolet (UV) irradiation, prolonged sun exposure, nutritional deciencies, hormone imbalance, pollution, and other factors like smoking, fast food, and even lifestyle [2, 3]. Wrinkling is related to skin aging due to loose elasticity, whereas graying and hair thinning are associated with hair aging due to reduced melanin production. These can be avoided or slowed by adopting preventative steps like taking antioxidant-rich supplements, eating a balanced diet, and adopting good skincare habits [4]. These changes lead to restrained free radicals which are the main cause of aging [5].

Aging refers to an inevitable yet natural and progressive process characterized by specic physiological changes occurring in living organisms with key features, such as senescence, telomere shortening, and altered gene expression at the cellular and molecular level which altogether leads to increased susceptibility to age-related disorders [6]. Chronological aging and photoaging are the two types of aging. Chronological aging is a natural and inevitable process, characterized by internal factors such as a reduction in the contents of collagen and elastin and reduced epidermal hydration leading to ne lines, thinning of skin and hairs, and reduction in elasticity. On the other hand, premature aging of the skin due to environmental aggressors, such as solar and ultraviolet radiations leading to leathery texture, wrinkles, and sunspots are clubbed under photoaging [7]. Recently, an interdisciplinary eld of research called Geroscience has been introduced for gaining insights into the fundamental processes of aging to identify potential interventions and strategies to promote healthy aging without chronic disability [8].

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1.1 Manifestations

Wrinkling, pigmentation heterogeneity, circulatory disorders, and ptosis are specic indications of aging. Wrinkling along with yellowing, coarseness, atrophy, and others is caused due to loss or reduction in the levels of collagen, elastin, and hyaluronic acid [9]. College and elastin are responsible for providing elasticity and strength to the epidermal and dermal layers of skin, while hyaluronic acid is essential for cutaneous hydration [10]. Commonly observed in females, fragility in nail plates is caused due to abnormalities in the maturation and dedifferentiation of keratinocytes in the matrix of the nails [11]. Another indication of aging is graying of hairs caused due to impaired melanin pigmentation. A study to indicate the elevation of hair graying due to smoking in young people also demonstrated the damage to melanocytes due to the generation of reactive oxidative species (ROS) because of smoking [12, 13].

Changes at the cellular and molecular levels such as elevation in oxidative stress, DNA mutation, reduction in mitochondrial biogenesis, and decrease in mitophagy have all been linked to aging and aging-related disorders such as osteoarthritis, osteoporosis, Parkinson’s disease, chronic obstructive pulmonary disease (COPD), atherosclerosis, and others [14]. Imbalances in the hypothalamic-pituitarygonadal axis are responsible for menopause in aged females due to elevation in estradiol and reduction in progesterone [15].

1.2 Mechanism ofAction

Although aging theories and concepts have not been fully elucidated, various mechanisms such as DNA damage, protein aggregation, and misfolding, electricity, Ca2+ signaling, mammalian target of rapamycin, the roles of non-coding RNAs, oxidative stress, apoptosis, alteration in mitochondrial permeability, etc. have been reported as major underlying mechanisms. Understanding these mechanisms could provide valuable insights for the development of new targets aimed at designing anti-aging drugs [16].

Various factors such as solar radiation, ultraviolet radiation, smoking, mitochondrial, metabolism, chemical toxins release several free radicals such as hydroxyl radical •OH, superoxide radical •O2-, nitric oxide radical •NO, peroxide radical ROO•, singlet oxygen 1O2, and others produce oxidative stress, causing DNA damage leading to misfolding and degradation of proteins which synergistically cause aging.

Damage to the DNA, impaired repairing of DNA, activation of an oncogene, certain epigenetic alterations, oxidative

stress, and shortening of telomeres are the key internal factors governing the progressive process of aging, Fig.1 [17]. Conversely, pollution, smoking, alcohol consumption, certain chemical compounds such as toxins, inammatory markers, ultraviolet radiation, and others are the group of external factors that produce cumulative detrimental changes in the morphology and physiology of skin cells leading to aging. Being the largest organ of the human body, from working as a shield to protect against pathogens and pollutants to regulating the body temperature, multiple approaches have been reported in the journals to prevent and treat senescence [18].

The initial theories of the by-products of metabolism and free radicals generated by mitochondria attacking the cell and its constituents suggest the production of highly reactive and unstable oxygen that oxidizes to form reactive oxygen species (ROS). The free radical theory of aging, rst proposed by Denham Harman, helps in understanding the mechanism of action [8]. The generated ROS species have the potential to damage the cells by lipid peroxidation, protein modications, and damage to the DNA.Elevated levels of ROS cause a reduction in the concentration of non-enzymatic proteins and hamper the antioxidant of the defense system, leading to an imbalance in homeostasis. ROS are known to attack the nitrogenous bases and sugar-phosphate backbone of DNA, leading to premature aging [19, 20].

Telomere shortening or replicative senescence during replication is an important process that governs senescence that leads to cellular senescence and mitochondrial dysfunction. Telomere shortening is also connected to mitochondrial malfunctioning via the peroxisome proliferator-activated receptor gamma coactivator 1a/b which regulates the biogenesis and role of mitochondria. Activation of p53 and DNA damage response pathways due to the shortening of telomeres suppresses the peroxisome proliferator-activated receptor gamma coactivator 1a/b and activation of p53 (a tumor protein) causing aging at the molecular level [21, 22].

The exposure and accumulation of ultraviolet radiation have been linked to the loss of structural integrity of the skin’s dermal connective tissue leading to the development of signs of skin aging, such as wrinkles, ne lines, and sagging. A well-known treatment for immunosuppression, exposure to solar and UV radiation at different wavelengths, goes in the process of aging skin cells. UV radiation, particularly UVB (constituting 5% of total UV radiation), can activate immunosuppressive cells like Tregs, myeloid-derived suppressor cells (MDSCs), and regulatory dendritic cells (DCreg). This activation has the potential to harm DNA and proteins by causing the formation of pyrimidine dimers and initiating a sequence of oxidative processes, ultimately resulting in oxidative stress [23–25].

Medicinal Plants, Antioxidant Potential, andApplications toAging

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Fig. 1 Mechanism of various factors inducing oxidative stress leading to aging

405

1.3 Conventional Anti-aging Methods

To reduce the signs of aging and promote overall skin health, several conventional anti-aging modalities are available in the market. They include topical skincare products with retinoids, hyaluronic acid, alpha hydroxy acids, and idebenone which not only provide moisture to the epidermal and dermal layers but also promote the production of collagen. Hormone replacement therapy, laser-in-light therapy, dermal llers, microdermabrasion, botulinum toxin injections, and chemical peels are available in the market for dermatological rejuvenation. Various pharmacological treatments have also been explored for anti-aging potential such as senolytic drugs, telomerase activators, and epigenetic drugs [25].

1.4 Potential ofMedicinal Plants asAntiaging Agents

While the mentioned treatment options are expensive and raise concerns about safety, researchers from all around the

globe are trying to exploit medicinal plants as anti-aging agents. The concept of using medicinal plants as anti-aging agents goes back to the ancient Ayurveda literature categorized as “Vayasthapana,” meaning to arrest aging or main- tain youthfulness, portraying the potential of the herb Centella asiatica having anti-aging properties [26]. Various studies on Withanolide, the steroidal lactones extracted from the roots of Ashwagandha, showed a 20% extension of the lifestyle by acting as agents that protect telomeres and repair DNA [27].

Different parts of four South African Plants C. glabrum, S. brachypetala, P. africanum, and P. capensis were evaluated for anti-aging potential in an in vitro study based on their activity against elastases, hyaluronidase, collagenase. The results revealed their ability to scavenge free radical and enzyme inhibitory, thereby helping in restoration of skin elasticity, and delaying the wrinkling [10]. Lycium bar- barum, a medicinal plant of Chinese origin, comprising of betaine, cerebroside, β-sitosterol, avonoids, riboavin, and other phytoconstituents, has been reported to decrease the oxidative stress while simultaneously boosting the efcacy

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of antioxidant enzymes. Furthermore, it inhibits cell apoptosis and reduces DNA damage, thereby acting as an anti-aging plant [28]. Certain Malaysian plants Cnestis palala, Urceola micrantha, Marantodespumilum, and Microporus xanthopus have reported to have anti-collagenase activities, highest anti-tyrosinase, acetyl- and butyryl-cholinesterase activity, all of which indicating anti-aging potential [29] (Fig.2).

Resveratrol, a phytoalexin stilbenoid, is a well-known ghter constituent from grapevine. It is a potent antioxidant that acts as a free radical scavenger, thereby inhibiting the DNA damage and protein degradation and protecting epidermal and dermal cells from oxidative stress. Simultaneously, it also activates SIRT1 which aids in regulating the cellular

Fig. 2 Mechanism of resveratrol acting as a well-known anti-aging agent

processes which collectively support cellular health and longevity.

Considering the current literature, this chapter shall focus on the mechanism and regulation of aging along with the effect of several medicinal plants acting as antioxidants to be further developed as anti-aging agents and restrict senescence. The purpose of this chapter is to indicate the enormous potential of medicinal plants and their phytoconstituents across the globe that can be built for dermatological characterization and upliftment. However, it should be noted that dietary antioxidants play a crucial role in preventing oxidative damage in the body, as the endogenous antioxidant defense mechanism alone may not be fully efcient.

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2 Plant Sources withAnti-aging

Potential

Plants are the source of many medicines to treat almost all kinds of diseases. Plants and their secondary metabolites have both enzymatic and non-enzymatic antioxidant defense mechanisms by which they can prevent the toxic effects of reactive oxygen species (ROS) like superoxide anion (O

Table 1 Plant sources having an anti-aging effect

Plant

Plant Bacopa monnieri

(Brahmi)

Curcuma longa (turmeric)

Emblica ofcinalis L. (amla)

Ginkgo biloba (gingko)

Glycyrrhiza glabra (licorice)

part(s) used

Whole plant

Rhizome Curcumin In vivo (rat) 200mg and

Fruit Tannoids (ascorbic acid,

Leaves Ascorbic acid, catechin,

Rhizome, root

Active phytoconstituent(s) Model Dose MOA References

Bacosides, Brahmine, and Herpestine

gallic acid, elaeocarpusin)

shikimic acid, lactone derivatives (ginkgolides), isorhamnetin, kaempferol 3-O-β-Dglucopyranoside, isorhamnetin-3-Oglucoside, myricetin, ginkgolide A, bilobalide

Glycyrrhizin, glabridin, and isoliquiritigenin

●-

), hydrogen

In vitro (human broblast cells)

In vitro (NB1RGB human skin broblasts)

In vitro (human dermal broblasts)

In vitro assay

peroxide (H

), hydroperoxyl radical (HO

2O2

●

), hydroxyl radi-

cal (OH), hydroperoxyl radical (●OH), peroxynitrite (ONOO), lipid peroxyl radical (LOO●), and nitric oxide (NO●). These free radicals attack DNA, protein, and lipids. Various plant metabolites like polyphenols, vitamins, carotenoids, and avonoids are reported as potent antioxidants [30]. Some plants that show anti-aging properties have been described in Table1 with the probable mechanism of action.

NP In a dose-dependent way, it

400mg of Curcumin/ kg body weight for 6months

0–40g/mL for 48h

0.1, 0.2mg/ mL for 24h

NP It acts by chelating with metal

boosts the activity of ROS-scavenging enzymes such as catalase (CAT), glutathione peroxidase (GPX), and superoxide dismutase (SOD)

It assists in the lowering of ROS generation, the scavenging of free oxygen radicals, and the blocking of lipid peroxidation. In human broblasts, curcumin promotes a cellular stress response via redox signaling through the phosphatidylinositol 3-kinase/ Akt (protein kinase B; PKB) pathway. It has the likelihood to avert cellular senescence. It also helps in C-reactive protein (CRP) reduction, an anti-aging inammatory marker

It inhibits the activities of GABA and monoamine oxidase-A (MAO-A). It also inhibited type I collagen collagenase and increased TIMP-1 levels; it inhibited cellular proliferation and protected procollagen 1 from UVB-induced depletion by inhibiting UVB-induced MMP-1

It decreased the levels of liver metalloproteinase and malondialdehyde while enhancing SOD activity to prevent oxidative stress. It inhibits production of ROS and the breakdown of MMP-1in human dermal broblasts

ions and scavenging free radicals. It also has tyrosinase and elastase inhibitory activity

[31–34]

[35–39]

[40–42]

[43–45]

[46, 47]

(continued)

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(continued)

Table 1

Plant Panax ginseng

(Asian ginseng)

Citrus sinensis L. (sweet orange)

Litchi chinensis (litchi); Nephelium lappaceum L. (rambutan); Tamarindus indica (tamarind)

Citrus reticulata Blanco (mandarin

orange)

Salacca zalacca (Gaert.) Voss (snake

fruit)

Citrus sunki Hort. ex Tanaka, Citrus unshiu Marcov, Citrus sinensis Osbeck, Citrus reticulata Blanco, and Vitis vinifera L.

(mandarin, grapes) Daucus carota L.

(carrot)

Carthamus tinctorius (safower)

Chaenomeles sinensis (Chinese

quince)

Prunus dulcis (almonds)

Panax ginseng Meyer and Crataegus pinnatida (Korean

ginseng, mountain hawthorn)

Plant part(s) used

Active phytoconstituent(s) Model Dose MOA References

Root Ginsenoside In vitro and

invivo (human volunteer)

Fruit Anthocyanins,

avanones, hydroxycinnamic acid,

In vitro human keratinocytes (HaCaT cell line)

and ascorbic acid

Fruit Ferulic acid, gallic acid,

epigallocatechin

Fruit D-Limonene,

In vitro (human skin broblasts)

In vitro assay

n-hexadecanoic acid

Fruit Chlorogenic acid In silico

Fruit Narirutin, hesperidin,

ascorbic acid

In vitro and invivo (cell culture and mice)

Root Carrot glycoprotein In vitro (cell

culture)

Seed oil Phenol In vitro assay

Fruit

Seed

β-1,4-xyloglucan

α-tocopherol

In vitro assay

Observational study (observational study)

Root, fruit

Ginsenoside In vitro and

observational study (human dermal broblasts, healthy human skin)

A. Pramanik et al.

0.05% PGLE for 8weeks

It can reduce lipid peroxidation. It is linked to the activation of the foxO3a

[48–51]

gene, often known as the longevity gene. It stimulates transformation of growth factor-β (TGF-β) in human skin broblast cells that promotes collagen production

15 and 30μg/mL for 7h

0.05, 0.01, and

0.007mg/ mL for 72h

It works by translocating NF-B and AP-1 and cleaving procaspase-3

It inhibits melanin synthesis in B16F10 melanoma cells by inhibiting tyrosinase and TRP-2; it is also efcient at

[52]

[53]

inhibiting elastase and collagenase

NP It inhibits collagenase and

[54] elastase and has antienzymatic action

NP It acts by MMP-1 inhibition [55]

33, 100, 300mg/kg for 10weeks

Increased antioxidant enzyme expression levels; skin thickness and wrinkle development are reduced,

[56]

while collagen levels are increased in a hairless mouse model exposed to UVB

0.3, 0.5, 1mg/mL

It neutralizes ROS and takes part in cell membrane

[57]

protection

NP It has the capability to inhibit

[58] collagenase assay and elastase assay

NP It has the capability of

[59] inhibiting the activity of dermal extracellular matrix proteases: elastase and collagenase

340kcal/ day of almonds

It works on wrinkle, decreases its severity in postmenopausal females

[60]

(58.9g) for 16weeks

100μg/mL for 12weeks

It prevents photoaging of the skin caused by UVB-exposure by regulating procollagen

[61]

type 1 and MMP-1 expression in NHDFs

Medicinal Plants, Antioxidant Potential, andApplications toAging

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(continued)

Table 1

Plant

Eleutherococcus senticosus (Siberian

part(s) used

Root Phlorizin In vitro (human

Active phytoconstituent(s) Model Dose MOA References

NP It works via miR135b

keratinocytes)

ginseng)

Citrus limon (lemon) Fruit Eriocitrin In vivo (mice) 4mL and

6mL/day

Sclerocarya birrea (marula)

Fruit, oil Quinic acid, catechin,

epigallocatechin gallate,

In vitro assay

100, 200μg/ mL

and epicatechin gallate

Zizania aquatica (black rice)

Camellia sinensis L. (black and green tea)

Grain Cyanidin -3-O-glucoside In vivo (mice) 15, 30, and

60mg/kg

Leaves Epigallocatechin gallate,

epigallocatechin-3-gallate

In vitro assay, invivo

50–300μM

for 6days (Caenorhabditis elegans)

Musa sapientum

Fruit Corosolic acid In vitro assay

NP It has inhibitory effects on

(banana)

Oryza sativa (Rice) Grain Vanillin and coumaric

In vitro assay

NP It has elastase inhibitory

acid

Withania somnifera (Ashwagandha)

Root Withanolide In vitro assay

(HeLa cell lines),

10–50μg

invivo

Tinospora cordifolia (Guduchi)

Stem NS In vitro assay

(PC12 cell lines)

10ng,

100ng, or

1μg

Ocimum basilicum L. (Tulsi)

Centella asiatica L. (Mandukaparni)

Aloe barbadensis miller (aloe vera)

Rosa gallica (French

rose)

Essential oil

Whole extract

NS In vitro assay

(K562 cells)

NS In vivo (human

PBMCs)

Gel Acemannan In vivo (human

volunteer)

Petal NS In vitro assay

(B16F10

100μL

0.02, 0.2,

2μg/ml

1200mg,

3600mg

NP It decreases MMP-1 gene

melanoma cells)

Hibiscus rosa sinensis, Hibiscus

Leaves Ferulic acid, p-coumaric

acid derivatives

In vivo (mouse skin)

NP It inhibits collagenase and

roseus

NP Not precise, NS Not specied

suppression that leads to improvement of the microenvironment and increases the proliferative potential of basal epidermal cells

It increases in aging-related scores (e.g., periophthalmic lesions) and delay inlocomotor atrophy

It blocks the activity of collagenase

It increases superoxide dismutase (SOD) and catalase (CAT) while decreases MDA and the activity of monoamine oxidase (MAO)

Black tea inhibits elastase activity, green tea helps in extension of life span through mitohormesis

MMPs activities

activity It resulted in an increase in

telomerase activity. It also shown anti-genotoxic properties in human peripheral blood cells against H

-induced DNA damage

2O2

It protects against cytotoxicity and DNA damage caused by radiation

Essential oil raises the apparent telomeres length and downregulates the telomeric repeat binding factor 1 (TERF

1) The extract has the capability

to increase telomerase activity almost nine-fold

Gel increases collagen production by decreasing collagen-degrading MMP-1 gene expression

expression

elastase. It also blocks UV radiation in the skin

409

[62]

[63]

[64]

[65]

[66, 67]

[68]

[69]

[70, 71]

[72]

[73]

[74]

[75]

[76]

[77]

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3 Phytoconstituents Having Potent

Anti-aging Property

very potent antioxidant anti-aging properties. Due to the hunger for an extended lifespan, people are increasingly drawn to natural antioxidants capable of promoting the gen-

Plants are supreme producers of secondary metabolites like alkaloids, glycosides, tannins, resin, volatile oil, phenolic and polyphenolic compounds, and avonoid compounds which are widely available in fruits, owers, seeds, vegetables, grains, and cereals. Out of these secondary metabolites phenolic, polyphenolic, and avonoid compounds possess

Table 2 Phytochemicals with anti-aging effects

Phytoconstituent Model Dose MOA References Ascorbic acid

(vitamin C)

α-Tocopherol (vitamin E)

Anthocyanins In vivo (fruit

Lycopene In vitro (A549

Resveratrol In vivo (gray

In vitro (HS68 broblast cell line)

In vitro

ies)

cell line)

mouse lemur)

10–40μg/ mL

NP It blocks the lipid peroxidation chain reaction [80]

30mg/dL It downregulates Mth gene and upregulates CAT, Rpn11, SOD1, and SOD2

75mg/day. 1nM and 10nM

200 mg/kg It stimulates the activity of nuclear factor erythroid-2 related factor 2 (Nrf2)

It promotes procollagen content and inhibits matrix metalloproteinase levels in skin broblasts. It also blocks hyaluronidase, elastase, and MMP-1

gene expression It reduces MMP-1 activity. It induces repair of base excision [82, 83]

and activates SOD, CAT to inhibit ROS.It activates anti-aging factor sirtuin1 (Sirt 1). It inhibits ROS by downregulating Akt/mTOR pathway

eration of new cells, preventing DNA damage, addressing mitochondrial dysfunction, inhibiting ROS production, and safeguarding against UV radiation without causing any harmful effects. Some active phytoconstituents that have been reported to possess very distinct activities to prevent aging are listed in Table2 (Fig.3).

[78, 79]

[81]

[84]

Fig. 3 Chemical structures of phytoconstituents used as antioxidant and anti-aging agents

Medicinal Plants, Antioxidant Potential, andApplications toAging

https://t.me/medicina_free

411

4 Conclusion

The purpose of our chapter is to indicate the enormous potential of medicinal plants and their phytoconstituents that can be built for dermatological characterization and upliftment. While various plants and their phytoconstituents have been studied exhaustively for their antioxidant potential to further develop as anti-aging agents, additional investigations are required to develop optimum extraction methods, to elucidate the molecular mechanisms of action of medicinal plants having antioxidant potential. A holistic approach to healthy aging, including proper nutrition, sun protection, regular exercise, and other lifestyle factors, remains essential for maintaining overall health and well-being as we age. While the above-mentioned list of phytoconstituents such as polyphenols, avonoids, carotenoids, and tocopherols, among others, has shown promising free radical scavenging properties in various studies, it should be noted that omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) also have the antioxidant potential but have not been exhaustively characterized yet. Retinol, hyaluronic acid, niacinamide, and ceramides are some of the versatile synthetic compounds that are well incorporated to address skin concerns such as signs of aging, dryness, uneven skin tone, and sensitivity. There are numerous unknown medicinal plants with ROS-scavenging potential that can be further expanded as anti-aging agents with comprehensive research. The major classics of Indian traditional medicine such as Charak Samhita and Sushruta Samhita mentioning over 700 herbs have elucidated the role of over 200 herbs aiding in skin wellness depicting promising prospects as anti-aging agents. A detailed insight into those unexplored sources may open a new path to the development of novel anti-aging therapeutics.

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