Skin Aging and Regenerative Medicine

Much More Than “Skin Deep”

Our skin is the body’s first barrier against environmental stressors and by far the largest human organ. Consisting of three layers– epidermis, dermis, and the hypodermis, –the skin protects us against pathogens, injury, UV-radiation, and much more.

The layer we can see with the naked eye is the epidermis. It provides a barrier against pathogens, UV radiation, and water loss. The epidermis contains sensory receptors that respond to touch, pressure, and pain. When exposed to sunlight, cells in the epidermis convert a precursor molecule into vitamin D. The most prevalent cells in the epidermis are keratinocytes–responsible for the production of keratin and giving the skin its strength and waterproof properties. Other cell types here include melanocytes (melanin production), Langerhans Cells (immune cells), and Merkel Cells (nerve cells).

The dermis serves as structural support; it gives our skin strength and elasticity with its network of collagen and elastin fibers. Other extracellular components include blood vessels, nerve endings, and sweat glands. With age and subsequent collagen loss, our dermis atrophies and gives rise to the appearance of crepe and wrinkles. It is also home to nerve endings that sense temperature, touch, and pain. Vessels and glands in the dermis allow us to regulate our body temperature and nutrient supply. Much of the structural function of the dermis can be attributed to fibroblasts, cells that produce and maintain the collagen and elastin fibers in our skin.

The hypodermis–the deepest layer in our skin–consists primarily of adipose tissue (fat cells) and serves as a cushion and anchor to protect us. The hypodermis insulates our inner organs, anchors the skin to the body, and houses larger blood vessels and nerve endings that facilitate nutrient supply and sensation to the upper layers of skin.

The skin hosts our lymphatic and vascular systems. Nerves in the skin are responsible for our sensory responses, from pain to pressure to temperature and touch. Skin regulates our body temperature in different environments and keeps the body in a state of homeostasis, all the while facilitating a complex network of signaling and secretion systems. In short–taking care of our skin goes far beyond beauty maintenance. Skin health is a fundamental first indicator of overall regulatory function within the body. The health of our skin is, in turn, a mirror to what goes on underneath.

Effects of Aging on Skin

Skin aging is a complex process and chain of molecular mechanisms influenced by both intrinsic (mutations, cell metabolism ect.) and extrinsic (UV radiation, pollution, chemicals) factors. Skin quality declines with aging due to chronological aging, photo-aging, hormonal changes, and environmental factors.  

UV and environmental pollutant exposure cause DNA damage to cells and generation of free radicals and ROS (reactive oxygen species). Free radicals and ROS further break down collagen and elastin in our skin. Age-associated lowering of hormone levels result in epidermal thinning and decreased skin hydration. Intrinsic aging happens as tissue loses dermal mast cells, collagen production, and fibroblasts overtime.

At the cellular level, aging is essentially progressive cell degradation and loss of regenerative capacity. As skin aging progresses, the regenerative capacity of skin cells lessen due to a gradual decrease of satellite cells and functioning stem cells. Under normal conditions, our body constantly replaces damaged cells and maintains the proper functioning of tissues. However, as we age, ROS and glycation (sugar-fueled chemical reactions) can damage our cells and decrease their proliferative potential.

This damage, along with the natural shortening of protective structures on our chromosomes (telomeres), and programmed cell death (apoptosis), contributes to skin aging. Among the visual manifestations of skin aging are wrinkles, fine lines, loss of elasticity, and loss of hydration.

Fines Lines and Wrinkles

Collagen and elastin are the pillars that give our skin structure and form. Collagen and elastin production in the tissues decrease by 1% each year with age, leading to a loss of integrity and structure in the skin. As epidermis thins and skin lose elasticity, skin folds and develops visible creases.  Wrinkles less than 1mm in depth and width are roughly defined as “fine lines.”

Loss of Elasticity

Often referred to as skin laxity, loss of elasticity is mainly caused by the breakdown of collagen and elastin fibers in the skin over time. Collagen is the most abundant protein in our skin; over time, collagen fibers can become disorganized and lose density. Elastin is a stretchy protein that resembles a rubber band, providing stretch and recoil to the skin. As elastin is broken down, the skin loses its ability to bounce back. The thinning of subcutaneous fat–which sits in the base layers of our skin–also results in the appearance of sagging skin and laxity.

Discolouration

Aging skin often shows changes in color, in the form of dark spots called senile lentigo and a condition known as melasma. These changes are common signs that our skin is getting older due to exposure to sunlight. As cellular aging and cellular senescence progresses, The interaction between melanocytes, which are cells that give skin its color, and other aging skin cells, like old fibroblasts, contributes to the changes in skin color as we age.

As we age, the cells that give our skin its color, called melanocytes, start to work less effectively; this is the reason why older adults tend to have paler skin.

Other cellular players, including keratinocytes, fibroblasts, and endothelial cells, engage in intricate interactions with melanocytes, significantly influencing the skin's pigmentation process. These intercellular communications are crucial for understanding the multifaceted nature of skin color alterations and related conditions as we age.

Wound Healing

Aging significantly impacts the body's wound healing capabilities, leading to a more complex and prolonged healing process. Key factors contributing to this include slower epithelialization, where the formation of new skin cells over a wound becomes less efficient due to reduced cell proliferation and migration. This is coupled with a decrease in collagen production, the protein vital for skin structure and wound healing, make the skin more prone to damage and scarring. The aging process also leads to reduced blood flow and changes in the immune system, known as immunosenescence, further complicating the wound healing process by limiting the availability of oxygen and nutrients to the wound and decreasing the body's immune response to infections.

In certain cases, advanced wound care treatments like growth factor therapies may be recommended to enhance healing in older individuals, highlighting the importance of tailored care strategies to address the unique needs of the aging population in wound management.

Regenerative Medicine and
Skin Health

The next generation of skin anti-aging treatments and products seek to harness the power of one’s own cells. Aging is, at its root, the gradual loss of regenerative ability in our own cells. Decades of research have shown that it is indeed possible to reverse the fundamental mechanisms of aging and tap into allogeneic (self) cell sources as the new standard of skin health rejuvenation and regeneration.

Platelet-rich plasma (PRP) treatments

PRP treatments are an early treatment option consisting of plasma (liquid portion of blood) and platelets (blood cells), sourced from a patient's own blood (autologous). Platelets function to clot blood at injury sites in the body, and promote cell regeneration and proliferation to trauma sites.

Clinicians draw blood, and spin the sample rapidly in a device called the centrifuge. The desired portion of platelet rich plasma are separated from the blood, and reserved for treatment. Many know of PRP treatments in the context of the “vampire facial,” in which microneedling is performed on the skin, and the PRP is applied after to promote cell turnover and tissue regeneration. Studies have shown that this procedure results in increased facial skin laxity and thickness.

PRP has also been used in treatment for musculoskeletal injuries, osteoarthritis, chronic tendon injuries, hair loss, fertility, and post-surgical healing. Whilst PRP remains a promising autologous treatment source, the lack of understanding behind its action mechanisms and composition limits its usage on a wider scale. PRP is difficult to characterize and standardize, and batch variability is great given the limited knowledge we have.

Cell-derived Exosomes and Growth Factors

Extracellular vesicles (EVs), otherwise known as exosomes are emerging as a promising new approach to cell-based therapies. Often collected from a proliferated cell population, the secretome (complete set of molecules secreted by cells) can be used in a wide variety of regenerative therapies from wound healing, sport medicine, to aesthetic applications.

Exosomes are responsible for extracellular signaling and intracellular shuttling; they are the delivery vehicles between our cells. They can contain and deliver key cellular elements like growth factors, proteins, and matrix molecules while also providing genomic components like DNA, RNA and MicroRNA. 

Studies show that these cell-free elements, like exosomes and growth factors, derived from a person's own stem cells hold significant therapeutic potential, helping support cell migration, proliferation, and regeneration.

Some skin conditions currently being researched alongside EVs/Exosomes include wound healing, scarring, burn healing, psoriasis. 

Advanced Stem Cell Uses

Stem cells are special cells in the body that have the unique ability to develop into different types of cells and to continuously self-renew. They serve as an internal repair system, dividing to replenish other cells in our lifetime. This makes them essential for growth, healing, and tissue repair.

Advances in the field of stem cell therapies for skin come from techniques initially developed for advanced wound repair and surgical aftercare. Due to the self-renewal capabilities of adult stem cells-isolated from sources such as bone marrow, adipose tissue, and the hair follicle-stem cells facilitate cell repair and migration at wound sites.

Aside from advanced wound-healing therapies, stem cells also have potential to treat aging skin and facilitate cell repair and cell migration to sites of collagen and elastin loss. At its root, skin aging is a cumulative representation of skin damage and a loss of proliferative ability in our epidermal cells; stem cells have the potential to speed up the body’s own repair process and help us fight against the biological mechanisms of skin aging.

Current Treatments for Skin Health and Appearance

Preventative Measures

Sunscreen: Serves as a barrier against UV and free-radical damage, one of the most effective measures against photo-aging and DNA damage.

Limiting Smoking and Alcohol Consumption: smoking and alcohol consumption can accelerate the effects of skin aging by disrupting lipid production and inducing inflammation

Topical Treatments

Retinoids (Retinol, Tretinoin, Adapalene): Derived from vitamin A, retinoids are among the most studied anti-aging ingredients. They can reduce fine lines and wrinkles, improve skin texture, and stimulate collagen production.

Antioxidants (Vitamins C and E, Ferulic Acid, Resveratrol): These help to neutralize free radicals, reduce inflammation, and protect the skin from UV damage and environmental pollutants.

Peptides: Small chains of amino acids that can stimulate collagen production and help repair skin.

Hyaluronic Acid: A powerful humectant that attracts moisture to the skin, helping to hydrate and plump the skin, reducing the appearance of fine lines and wrinkles.

Alpha Hydroxy Acids (AHAs) and Beta Hydroxy Acids (BHAs): These exfoliants remove dead skin cells, improve skin texture, and promote new cell growth.

Neuromodulators and fillers

Botulinum: Botox (and similar injectable alternatives) is derived from a neuromodulator produced by the bacterium Clostridium botulinum. When injected in small, controlled doses, it temporarily paralyzes muscles. It blocks chemical signals responsible for triggering muscle contractions. This relaxation of the muscles reduces the appearance of wrinkles, especially dynamic wrinkles that are formed by facial expressions.

Dermal Fillers:
Dermal fillers are gel-like substances injected beneath the skin's surface to restore lost volume, smooth lines, soften creases, or enhance facial contours. Different types of fillers are available, with hyaluronic acid being one of the most common. Hyaluronic acid fillers are the most popular as HA is a compound naturally found in the body. Other fillers such as those made with calcium hydroxylapatite or poly-L-lactic acid also claim to stimulate collagen production and are used for deeper lines and wrinkles.

Surgical Procedures

Surgical procedures are also used to cosmetically eliminate the visual effects of skin aging. Popular treatments include:

Fat grafting:
autologous fat injections in which a patient’s own fat is harvested from another area of the body via liposuction, then purified and injected back into the face to restore volume loss and support sagging skin.

Rhytidectomy (face-lift):
A face-lift is an invasive surgical procedure involving the removal of excess facial fat and re-shaping of facial skin. Skin is pulled back on the face or neck and tightened. It is done to improve the visible signs of skin aging and sagging; while quality of the skin does not change, the procedure aims to reduce jowling and create a firmer look.

Microneedling

Involves creating controlled wounds to the skin via tiny punctures. Microneedling has been widely studied and shown to stimulate collagen production and improve skin texture via increased cell turnover. It also allows for better absorption of vitamins, serums, and other treatments beyond the skin barrier. Often, microneedling is paired with other serum-based treatments such as PRP (platelet-rich plasma).

Chemical Peels

Application of a chemical solution to remove the top layers of skin to reveal new skin underneath. Peels are essentially acidic solutions that react with surface skin cells to break down bonds and peel away dead skin layers.

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