Vitamin C (L‐Ascorbic Acid) and Vitamin E2

Ascorbic acid is known for its antioxidant properties. It is available naturally in citrus fruits and leafy green vegetables [21–23].

Vitamin C can effectively counteract sun‐induced acute effects like redness, sunburn, and tanning, as well as chronic photoaging [24]. Formulation challenges in topical cosmeceuticals include providing a high concentration. At least 10% of the nonesterified optical isomer which is adequately stabilized converts to inactive brown dihydroascorbic acid on exposure to air. Secondly, vitamin C is hydrophilic, so its penetration into the skin is low. Ferulic acid and alpha lipoic acids can be combined to stabilize vitamin E and vitamin C solutions. Vitamin E also has properties akin to vitamin C, and in combination their effect manifests multifold [25]. Vitamin C regenerates oxidized vitamin E, so the combination in a cosmeceutical formulation is synergistic, particularly for ultraviolet (UV) protection. Both these agents also share depigmenting properties which is due to their action at different stages of melanogenesis. Vitamin C acts by interacting with copper ions to reduce dopaquinone conversion to DOPA (dihydroxyphenylalanine). It also blocks dihydroxyindole‐2‐carboxylic acid (DHICA) oxidation in addition to having antioxidant properties. Stimulation of neocollagenesis is another well‐known property of vitamin C. It also plays a role in pigmentary and inflammatory skin disorders due to the above mentioned mechanisms.

Ascorbic acid and its derivatives, magnesium ascorbyl phosphate (MAP) and ascorbyl tetra isopalmitate, are used extensively in topical antiaging cocktails. MAP caused alterations in the visco elastic‐to‐elastic ratio, which suggests its action in the deeper layers of the skin [26].

Alpha Lipoic Acids [1, 27]

Alpha lipoic acid and its reduced form, dihydrolipoate, are both potent free‐radical scavengers and also have anti‐inflammatory properties. It inhibits tyrosinase by chelating copper and decreasing DOPA quinone derivative formation [28]. It increases the glutathione (GSH) level which reduces UV radiation sensitivity [29]. It also has a role in stabilizing vitamin C and E in preparations and an exfoliant action.

Ubiquinone and Idebenone

Coenzyme Q10 is an essential component of the mitochondrial respiratory chain and forms an important defense against superoxide radicals. Ubiquinone (from ubiquitous, i.e. universally found) is naturally derived whereas idebenone is a synthetic derivative. Idebenone’s penetration into the skin on application is much better because of its low molecular weight. Also, nanostructured lipid carriers enhance skin permeation along with increasing the stability of idebenone [30].

0.5–1% idebenone lotion used twice a day for six weeks was effective in reducing fine lines and wrinkles, with improvement in skin hydration [5].

Collagen Repair Molecules

With age, collagen degrades and the resultant volume deficit leads to fine lines and wrinkles. Products that stimulate collagen production would be useful in these cases.

Growth Factors

Growth factors are important as they guide tissue remodeling in wound healing. On the other hand, their quantities are reduced in intrinsic and extrinsic aging along with fibroblasts number and activity. So supplementing them could mean reversal of the damage. They can be obtained from cultured human fetal fibroblasts biotechnologically [31, 32].

A study assessing the effect of topical growth factors on photodamaged skin found that 11 of the 14 study patients showed clinical improvement in at least one facial area. The periorbital region showed a statistically significant improvement in the depth and number of textural irregularities or fine lines. Biopsies revealed new collagen formation in the grenz zone (37% increase in thickness) and thickening of the epidermis by 27% [33]. Other studies have corroborated this effect on aging [34, 35].

Kinetin (N‐furfuryladenine growth factor) is a plant growth factor that has shown antiaging effects on skin on topical application. It acts by scavenging reactive oxygen species (ROS) [6]. It has a synergistic antiaging effect with niacinamide [36].

Peptides

Peptides are proteins and small amino acid sequences. They have an effect on the stimulation of collagen production or downregulation of collagenase activity. They also modulate cell migration, proliferation, and inflammation [37–39].

There are three types of peptides:

1. Signal peptides. These are fragments of collagen and elastin which activate fibroblasts and stimulate healing. Hence, they increase collagen formation.
   
2. Neurotransmitter affecting peptides. These interfere with neurotransmitter release with a resultant decrease in muscle movement.
   
3. Carrier peptides. These peptides deliver trace elements like copper into the skin which activates enzymatic pathways of wound healing and enhances collagen production.

The most stable and widely used signal peptide is lysine‐threonine‐threonine‐lysine‐serine (KTTKS) found on type I procollagen. Linking of KTTKS to palmitic acid (pal‐KTTKS), or their application following microneedling to bypass the stratum corneum barrier, can enhance penetration.

Investigators in a 12‐week, double‐blind, placebo‐controlled, split‐face, randomized clinical study of 93 Caucasian women found that a moisturizer containing pal‐KTTKS showed significant reduction in fine lines [40].

The tri‐peptide GHK (glycyl‐l‐histidyl‐L‐lysine) helps deliver copper to the cells by readily complexing with it [41]. Enzymes like superoxide dismutase and lysyl oxidase require copper as a cofactor. It was found that copper‐complexed GHK‐Cu suppresses inflammation by decreasing the level of transforming growth factor β and tumor necrosis factor (TNF)‐α. Tri‐peptide GHK also reduces oxidative damage by quenching toxic products of fatty acid peroxidation and modulating iron levels. It serves as the chemoattractant for inflammatory and endothelial cells and increases fibroblast proliferation [42].

Palmitoyl tetrapeptide‐7 is able to downregulate IL‐6 in vitro in both resting and inflamed cells. Many cosmetics include this as an ingredient, with claims of increased skin firmness, smoothness, and elasticity.

Acetyl hexapeptide‐3, a neurotransmitter‐inhibiting peptide, is patterned from the N‐terminal end of the protein SNAP‐25.

In a randomized placebo‐controlled study on 60 Chinese patients by Wang et al., Argireline (a synthetic hexapeptide) showed an anti‐wrinkle efficacy of 48.9%, compared with 0% in the placebo group in the subjective analysis [43].

Future Molecules: Ribonucleic Acid

There has been ongoing research into genes controlling aging and how ribonucleic acid interference (RNAi) can benefit the development of antiaging cosmeceuticals. Ribonucleic acid here is used to block or inactivate a target gene. The study of genomics has helped identify potential targets for this approach. Delivery remains a major hurdle for these molecules; oligonucleotides can be injected directly or vectors, like viruses, used. Ribonucleic acids have been employed as small interference RNA and micro RNA as antiaging cosmeceutical ingredients [44].

Stem Cells

A stem cell is a sort of unprogrammed cell that has the potential to become any type of cell in an organ or in the body. The embryonic stem cells are pluripotent, and can differentiate into any cell type in the body, whereas the skin stem cells, which reside in the basal layer of the epidermis, only form epidermal cells [45, 46].

With age their numbers dwindle and they are not able to replenish the superficial layers as optimally with daughter cells. To replace these cells from outside remains a viable option using embryonic stem cells.

Cell therapy is a novel treatment where genetically engineered cells can be introduced to replace aged cells in the body. They overcome the limitations of gene therapy and RNAi. Stem cells may exert their beneficial effects on tissue regeneration through complex paracrine mechanisms in addition to their proposed direct cellular effect [47].

Secretory factors released from stem cells could be important mediators as has been seen in wound healing using embryonic stem cell‐derived precursor cell therapy [48]. Furthermore, stem cells synthesize and secrete a variety of extracellular matrix proteins, cytokines, growth factors, and other bioactive proteins that contribute to the healing process; the local environment created by these secreted factors may govern the fate and function of individual stem cells [49].

However, the use of human embryonic stem cells in cosmeceuticals has been shrouded in the controversy of ethical issues. Adipose‐derived stem cells surpass the issue by their easy accessibility and ready abundance. Their soluble factors have shown stimulation of both collagen synthesis and migration of dermal fibroblasts with increase in angiogenesis, improving wrinkling, and accelerating wound healing in animal models. In addition, there is inhibition of melanogenesis and protection of dermal fibroblasts from oxidative stress induced by chemicals and UVB irradiation [50, 51]. Further research and reviews will ascertain if this beneficial effect is carried on to human skin.

Plant extracts, plant stem cells, and plant stem cell extracts, seemingly the same, are in fact all different. The first and the last have been used in cosmeceutical preparations. The former have been used in cheaper preparations with the downside of lacking standardization, contamination with pesticides and heavy metals, and being ineffective or having nonreproducible results.

Plant stem cell extracts, on the other hand, are obtained from plant stem cells which have been cultured in the lab under standardized conditions after sterilizing the plant part of origin. They do not contain plant stem cells per se but their filtered, homogenized, centrifuged, and lyophilized extracts, which are then incorporated in different formulations. They provide pure, standardized ingredients with dose consistency.

Extracts have been prepared and used from grapefruit seeds, lilac leaf, swiss green apple, and berries such as strawberries, raspberries, and blueberries. It has been seen that wild plant extracts have a higher antioxidant action.

The role of most of these plant‐derived stem cell extracts is to protect existing human stem cells residing in the basal layer of human skin from free radical‐induced DNA damage.

The Klotho Gene

The Klotho gene, named after the Greek goddess Klotho who controlled the lives and destinies of humans, was first discovered in mice. It was shown that dysfunction of this gene causes premature aging symptoms and shorter lifespan in the mice [52].

This gene codes for many things, including a transmembrane protein inhibiting phosphorylation of insulin‐like growth factor 1.

The transmembrane form of Klotho protein functions as a co‐receptor for FGF23 and regulates phosphate, calcium, and vitamin D metabolism. The extracellular domain of Klotho protein is shed and secreted into the systemic circulation, where it functions as an endocrine factor. The secreted Klotho protein controls multiple ion channels and growth factor signaling pathways including insulin, IGF‐1, and Wnt, potentially participating in the biology of cancer and stem cells.

There have been claims by cosmetic industries that red snow algae from the Swiss Alps increase the expression of Klotho gene in human cells, thus promoting antiaging processes in the cells. However, there are no scientific studies to confirm this.