Research on aging including therapies for external, internal and emotional concerns continues to expand to accommodate Baby Boomers’ demands to stay young as long as possible. The youngest Boomers are turning 50, and while many may be looking forward to retirement, rest assured that none are looking forward to aging. With intrinsic and extrinsic aging, certain deteriorations may occur giving rise to disorders and illnesses such as arteriosclerosis and cardiovascular disease, ocular disorders, skin laxity, cellulite, arthritis and joint problems, to name a few. All of these conditions have one thing in common: connective tissue. Because connective tissue deterioration in the body can have far-reaching, systemic effects, much research has been devoted to decoding its mechanisms.

Studies on connective tissue have produced valuable data, which have stimulated the creation of treatments for preventive and rejuvenative healthcare. Treatments have focused on external therapies such as skin care and esthetic medicine; others concentrate on internal solutions, delving into nutrition, medication, diets and supplements; lastly, a few programs have examined patient psyche to reduce emotional stress and anxiety.

While these treatments on their own may produce some results, it is plausible that even greater results can be achieved if used together in an inclusive model of care. In fact, some in the medical community already use comprehensive systems or multidisciplinary approaches including alternative interventions to address systemic health and see real value in offering inclusive care, citing that individual protocols lack synergy or continuity of care, topically, internally and emotionally. Such is the case in our office as well-documented therapies and agents are combined in an all-encompassing, multidisciplinary approach. In this way, inclusive care may be the most appropriate strategy for cell and connective tissue remodeling, repair and prevention of future damage. 

Connective tissues are the structural components of the body and are found in the extracellular matrix. These tissues provide the systemic scaffolding or framework the body needs to literally hold it together, joining layers of muscles and organs, providing the vascular highways that deliver nutrients to every part of the body. There are three types of connective tissue: loose, fibrous and specialized. Loose connective tissue consists of collagenous, elastic and reticular fibers, which are responsible for holding organs, epithelial tissue and underlying layers together. Fibrous tissue is found in tendons and ligaments and features dense collagen formations. Specialized tissue includes bone, adipose tissue, cartilage and blood vessels.

These tissues deteriorate due to intrinsic and extrinsic aging. Literature shows that both intrinsic aging and extrinsic stressors deteriorate connective tissue in the same way they damage cell membranes.¹ For example, cutaneous deterioration occurs with photo damage, as does damage to connective tissue.² Also, during senescence, human skin becomes fragile because of fragmentation and the loss of type I collagen fibrils, which make the connective tissues strong and resilient. Fragmentation promotes oxidation and in turn, elevates matrix metalloproteinases-1 (MMP-1) levels. One study demonstrates that dermal fibroblasts express increased levels of collagen-degrading MMP-1 in aged (>80 years old) compared with young (21 to 30 years old) human skin in vivo, and MMP regulators also become elevated.³ As a result of these findings and others, it is now believed that aging is not just relegated to cells, rather it includes the extracellular matrix and it is plausible that the connective tissue microenvironment may play a vital role in the biology of not only cutaneous aging but also systemic disease.

Pathophysiology
Many connective tissue diseases feature similar and overlapping routes of damage, which may be the result of an immune system disorder and/or the weakening of collagen. Connective tissue deterioration can also occur because of oxidation, inflammation and dehydration.⁴ Some diseases are inherited such as Marfan syndrome and Ehlers-Danlos syndrome, and others have no known cause: systemic lupus erythematosus, rheumatoid arthritis, scleroderma, polymyositis and dermatomyositis.⁵ Connective tissue damage may also occur because of physical injuries such as those that may be experienced during sports activities. The risk of connective tissue damage may increase with detrimental lifestyle behaviors such as poor diet and smoking.^6,7 Cultural stress, environmental aging and hormonal aging also have specific influence on connective tissues.^8,9

For the sake of organization, a patient’s degree and risk of connective tissue damage can be categorized in three ways: external, internal and emotional. For example, in patients with poor connective tissue function, externally, the cutaneous layer may exhibit laxity, deep wrinkles and in places, cellulite may be present. Internally, there may be inflammatory disorders that involve the vascular system, joints, tendons, ligaments, blood and hormones. Emotionally, unabated stress has been well documented to cause hormonal imbalance, telomere shortening and sleeplessness, which can affect healing, cell replication and immunity.^10,11 Sleeplessness is complexly associated with depression, dementia, heart problems,¹² pain and stroke—all of which can have specific influence on connective tissue remodeling, repair and damage prevention.

Connective Tissue Repair & Remodeling
Connective tissue houses the bulk of the body’s water. As we age, cellular and connective tissue water loss occurs. When dehydrated, cells may not function properly or replicate normally. Connective tissue that has experienced water loss may become fragile, as collagen fibers grow rigid and elastic fibers lengthen and become lax. Free radical damage, inflammation and other factors may stimulate repair, but repair processes may be unpredictable, insufficient, in excess and in disorder. As a result, connective tissues, overall, may lose their resiliency and resistance to compression and tension, further increasing the risk of damage.

Tissue remodeling is a repair response to damage. Connective tissue repair involves the immune system because damage or injury stimulates the fibroblasts and synovial cells to release pro-inflammatory cytokines, prostaglandins, collagen and collagenase.^13,14 This initiates a multifaceted, overlapping damage-control process. Mast cells release histamine within the connective tissue and an increase in capillary permeability occurs. Dilated blood vessels carry white blood cells to the damaged areas. The release of interleukins and transforming growth factor beta (TGF-beta), a hormonally active polypeptide, stimulate connective tissue growth factor (CTGF) and other polypeptide growth factors, which promote cell growth, adhesion, migration and angiogenesis.^15,16 CTGF upregulates the release of MMPs and their inhibitors.¹⁷ MMPs occur naturally within tissues and exert both pro- and anti-angiogenic functions. Inflammation accumulates in an effort to prevent further damage or destruction of tissue. Finally, through a complex process of interactions, connective tissues utilize nutrients to repair damage as MMP inhibitors help dissipate inflammation. In wound healing, fibrinogen converts to fibrin (thread-like proteins), and forms a mesh-like structure to rebuild tissue. A disproportionate amount (too little or excessive) of inflammation will actually inhibit repair and remodeling and delay healing. The exact process of remodeling and repair remains unclear and is undoubtedly more complex than described here. As new research is performed, the exact mechanisms mediating these responses may be discovered.

What is known is that fibroblasts are central to the connective tissue damage response. Also, proteoglycans support repair as they supply the necessary glycosaminoglycans necessary to rejuvenate and create new collagen fibers. Going further, repair also involves the water transport systems as water homeostasis between the extracellular matrix, cells and connective tissue must be achieved for proper tissue regeneration.

Fibroblasts
Because fibroblasts are the main cell type found in all kinds of connective tissue and are involved in the regulation of extracellular matrix protein production, in aged, diseased or damaged connective tissue, fibroblast activity may be reduced and unresponsive to epidermal growth factor, and this may cause poor wound repair.¹⁸ Studies have shown that oxidative DNA damage contributes to replicative cessation in human diploid fibroblast cells, but this process can be slowed with the use of antioxidants and spin-trapping agents such as alpha-phenyl-t-butyl nitrone (PBN), which can act like an antioxidant.¹⁹ Conversely, studies have also shown that fibroblasts use free radicals to stimulate proliferation,²⁰ but this is a complex process involving a balance of precise mechanisms—a process just short of damage.

Fibroblasts are active players in adaptive immunity and can transition acute inflammation to acquired immunity through the cells’ ability to produce chemokines and the extracellular matrix. In response to any damage or injury that results in inflammation, the fibroblasts—which are versatile connective tissue cells and can differentiate into an array of other types of connective tissue cells including cartilage, adipose tissue, bone and even circulate precursors within blood—initiate an adaptive immunity response to commence tissue repair.²¹

Proteoglycans
Proteoglycans are the main component of the extracellular matrix’s ground substance and are important in the regeneration and proliferation of collagen and, thus, connective tissue. Proteoglycans are heavily glycosylated glycoproteins or mucopolysaccharides and are also referred to as glycosaminoglucans (GAGs). GAGs are predominantly made of hyaluronate and sulfurs.

The building block for hyaluronic acid is glucosamine. Studies have shown that the long-term use of glucosamine sulfate can help repair tissue and reduce symptoms in osteoarthritis.²² Literature also indicates that glucosamine sulfate inhibits ICAM-1 production in conjunctival epithelial cells in vitro. It is therefore plausible that future clinical study may show that glucosamine sulfate functions well to abate systemic inflammatory conditions caused by pro-inflammatory cytokines.²³

Sulfur is found in every living cell in the body and it plays a key role in collagen synthesis and immunity.²⁴ Early studies have also indicated that sulfur-containing foods like garlic, onions, meat and cruciferous vegetables can offer anti-inflammatory and detoxifying benefits. The sulfur content in GAG molecules allows them to possess a high negative charge density, so they repel each other and cause a space-filling function, permitting them to store water and provide connective tissue with cushioning compression strength and resiliency.²⁵

Collagen Fibers
There are many kinds of collagen found within the body. They consist of long chains of proteins derived from amino acids and are found in the extracellular matrix. Collagen, together with elastin, gives connective tissues great tensile strength. Most kinds of collagen are either types I, II or III. Both the fibroblasts and epithelial cells make collagen.²⁶ Together with GAGs and hyaluronic acid, the dermal matrix houses the collagen and elastin needed for a resilient epidermis. Collagen and elastin consist of amino acids, which serve to protect connective tissues (blood vessels, nerves, tendons and ligaments, and dermis).²⁷ Also protective, estrogen has been shown to prevent a decrease in skin collagen in postmenopausal women, thus helping to maintain skin thickness. In addition, estrogen increases acid mucopolysaccharides and hyaluronic acid in the skin, which suggests that it could play a role in maintaining stratum corneum barrier function and connective tissue resilience. It has been postulated that estrogen increases cutaneous wound healing because of its cytokine-regulating role.²⁸ In fact, topical estrogen has been found to accelerate and improve wound healing in elderly men.

Also of note, essential fatty acids and antioxidants act synergistically to moderate the induction of inflammatory mediators, decrease free-radical tissue damage and inhibit collagen and elastin breakdown from MMPs.

Cellular & Connective Tissue Water
Regardless of the precise mechanism of damage or location of damage; e.g., fibroblasts, extracellular matrix, collagen, the common pathway to deterioration in all tissues is water loss. It has been suggested that if general cellular health is addressed, simultaneous improvements in systemic, cutaneous and connective tissue health may be seen. This forms the basis of The Water Principle theory,²⁹ and also the reasoning behind using a multidisciplinary strategy for connective tissue remodeling, repair and damage prevention.

The Water Principle theory builds on Nagy’s Membrane Hypothesis of Aging, which discusses cell damage, intracellular waste accumulation and cell membrane permeability as the result of ROS-induced cross-linking and the residual heat formed during heat discharge of the resting potential.^30,31,32 The Water Principle develops Nagy’s theory, acknowledges that cell deterioration may be more complex, and goes further to suggest ways to slow or reverse cell and connective tissue damage using a systematic, inclusive program (external, internal, emotional) replete with therapies tailored to a patient’s specific needs and aimed at promoting efficient water regulation across all cells and connective tissue.⁸ In this way, connective tissue may be more adequately remodeled and repaired while damage is prevented.

Within an inclusive program congruent with The Water Principle, cytoprotective therapies, stress reduction and the inclusion of nutrients (vitamins, minerals and phytochemicals) in the diet are emphasized.^4,29 Simply, when oxidative stress is reduced and the body is flushed with nutrients topically and systemically, its nutrient-deprived cells and connective tissue can seize nourishment for remodeling and repair.³³ This theory postulates that cell and connective tissue fortifying therapies reduce water loss, but makes clear that the prevention of water loss in tissues goes beyond simply drinking water, as it is difficult for damaged cell membranes and connective tissue to retain any water until they are remodeled and repaired. This stabilization of water within cells and connective tissue may increase resiliency to damage offering protection from inflammation, oxidation and MMP formation.

Literature indicates that when ICW is addressed, cells are healthy and strong and immunity is functioning at the highest levels, promoting wound healing and tissue regeneration.^34-36 As a result, optimal cellular and connective tissue conditions are encouraged, plausibly uncomplicating and improving overall health.

Treatment & Management Strategies
The human body is a complex, overlapping network of systems, organs, cells, connective tissues and fluids. All systems intersect and rely on each other to maintain body homeostasis. Understanding this, the consideration of using combination therapies featuring nutrition, medication and alternative interventions is a natural choice. Such is the case within our office. We have found that improving connective tissue with singular methods or medications may not function long-term, and do not accomplish all treatment goals, which include:

• Increase cellular and connective tissue immunity
• Reduce inflammation and free radical damage 
• Normalize and fortify integument system
• Promote collagen formation
• Address hormonal imbalance and other internal diseases
• Encourage sleep
• Improve nutrition
• Offer relaxation and emotional support

These treatment goals can be achieved using the following three-pronged inclusive approach, which combines multidisciplinary interventions including external care, internal care and emotional care. This mode of treatment encourages cytoprotection and connective tissue fortification from every plausible aspect:⁸

1. External care—to address innate immunity; strengthen cutaneous defenses to external influences or invaders. Beginning with a daily skin care regimen, external care would include patient-specific cleansers, treatments and hydration to repair damage and protect and fortify the skin’s barrier function and connective tissue from external factors such as UV rays. External treatments may focus on collagen-deposition and formation encouraging agents and treatments.
2. Internal care—to encourage adaptive immunity. Diagnostic tests assist in determining systemic disease such as endocrine system or vascular disorders, so therapeutic, systemic care can be initiated. Therapeutic care may include nutritional guidance, supplements that encourage sleep and physical activity and prescription medication.
3. Emotional care—to support psychological and social balance. Stress reduction “feel-good” services such as those provided within the spa environment may be used, as well as activities like yoga, support group participation and counseling to nurture the psyche.

External Care
A tremendous amount of literature is available on enhancing cutaneous barrier function and protection from environmental aging. No doubt, as each year passes new agents and techniques will be introduced as the skin care industry proves to be an ever-changing market. Current methods include a variety of therapies and a wide range of options that may focus on exfoliation, lipid preservation, sun protection and cosmeceutical use. Topical solutions may feature everything from mechanical devices to chemical agents and botanical ingredients. Combination therapies are the norm with topical procedures and are based on the physician’s preference and skill. Some therapies may be used concurrently or in succession for a period of time for ultimate results.

Internal Care
Within the body, chronic inflammation can set off a litany of biological responses that may result in cell and connective tissue deterioration or disease. Therapeutic methods to stave off and reduce inflammation utilize nutrients that ensure the tissues have adequate amounts of basic building materials to re-strengthen, abate inflammation and improve cells and connective tissue turnover. Tissue maintenance and growth is promoted with amino acids.²⁷ Amino acids are essential building blocks for collagen and elastin, which are crucial in defending connective tissues such as the blood vessels, nerves, tendons and ligaments. It follows then that a diet rich in amino acids is desirable.

Amino acids such as cysteine (precursor of glutathione and taurine) and glycine (precursor of glutathione), methionine (precursor for the sulfur content of cysteine and glutathione) and proline (precursor for collagen) act as 1) building blocks for tissue regeneration and 2) precursors for endogenous antioxidants (in particular, glutathione).^37,38 GAGs (glucosamine) and lecithin are also important to add to the diet.³⁹ Lecithin has been well documented to repair cell walls, thus its focal role in repairing tissues. In fact, lecithin, which is mainly comprised of phosphatidylcholine, is a major component of cellular membranes.¹

In order to initiate remodeling and prevent damage, the incorporation of antioxidants, soluble and insoluble, in the diet is central to reducing the effects of oxidative stress and cellular and connective tissue water loss.⁴⁰ For example, vitamin C removes free radicals from the cell structures composed primarily of water and from areas containing body fluids; beta-carotene and vitamin E are active in the lipid or fatty parts of the cell membrane and in fat tissue; coenzyme Q10 protects mitochondria oxidation; vitamin A plays a large role in the repair of body tissues; and alpha lipoic acid boosts cellular energy, enhances immunity and muscle strength and improves brain function.^41-46 Alpha lipoic acid allows other antioxidants such as vitamins C and E to work better to improve growth and repair while it also prevents cell damage.¹ A diet rich in these antioxidant nutrients may assist in cellular repair, replication and prevent oxidation and subsequent damage.

Similarly, we also recommend the inclusion of healthful EFAs (essential fatty acids) within the diet with the reasoning that EFAs are found in the stratum corneum and cell membranes. EFAs have been shown to enhance the immune system, thus strengthening the skin’s barrier function.^1,8 Low ratios of omega-6 to omega-3 have been shown to reduce the risk of certain cancers, cardiovascular disease, arthritis and even asthma.⁴⁷

Ample literature exists indicating that sleep loss has the potential to promote degenerative health conditions and poor wound healing;^48-53 as such, in our office, we encourage the use of sleep-promoting ingredients to help fortify cellular immunity. Along the same lines, we also suggest an increase in B vitamins because of their known abilities to regulate cellular metabolism and for their immune system support. Additionally, the B vitamins may also play a role in regulating hormones and offering support for the nervous system.³³

Emotional Care
Because of its subjective nature, stress may be difficult for patients and physicians to classify. Scientifically, it has been graded as either acute, episodic acute, chronic or cultural stress.^8,29 Externally, it is known to produce reactions on skin such as increases in acne breakouts, and it also has internal implications with regard to hormonal imbalance.⁵⁴ Systemically, it has been suggested that stress creates microinflammatory pathways⁵⁵ and has been linked to telomere shortening which, together, demonstrate a causative relationship, producing cellular deterioration.⁵⁶

To explore the emotional response within systemic tissues, research has been performed to discover a plausible link between tissue health and the central nervous system. It was found that both the epidermis and central nervous system utilize the same communication molecules, which indicates there is indeed a mind-body connection, or Neuro-Immuno-Cutaneous-Endocrine network (NICE).  Specifically, emotions can be used to reduce stress and increase skin health, bi-directionally—mind-relaxing therapies improve skin condition and skin-conditioning therapies improve mind relaxation.^57,58 Because all systems, tissues and organs are connected, it can be postulated that stress reduction not only improves skin function and health, but also connective tissue health. For example, massage has been shown to increase the rate of healing, decrease depression, reduce stress, lessen pain and improve sleep in various studies and reviews.⁵⁹ Along the same lines, in our office, certain exercises such as yoga are also suggested to help reduce stress.

Inclusive Health Program
Within our office, patient-specific inclusive care programs are used to achieve cellular and connective tissue water homeostasis. In this way, we believe that cellular rejuvenation is promoted, as is connective tissue repair and remodeling. We do this by assisting patients in enhancing their immune systems and increasing systemic health. Within our program, nutritional guidance and dietary supplements are only one aspect of the combination therapy used. Every program is individualized for a patient. To customize the therapy, a thorough analysis of the patient’s external, internal and emotional concerns is performed through the use of a consultation, questionnaire and blood tests. Baseline measurements are taken and include the use of RJL Systems body composition analysis machines and measurements are taken periodically for the duration of treatment, in addition to questionnaires and photography, offering a tangible record of progress for each case. Based on our preliminary evaluation, a treatment roadmap that outlines external, internal and emotional care is devised.

Prescription medication is discussed and if congruent with the goal of creating optimal systemic health, then it is suggested. This includes prescription drugs needed to address hormonal imbalance, cardiovascular disease or chronic inflammation. Further evaluation and treatment by specialists is arranged if necessary. 

Weekly, if not daily prescriptions for cosmeceutical products and treatments are provided in addition to a schedule of in-house facial, body and massage services. We also provide a detailed dietary and nutritional summary that outlines foods, nutrients and supplements needed for the patient’s body needs, concerns and goals. Likewise, a recommendation for physical activity like yoga, tai chi and walking, is offered to help augment internal treatments while reducing stress levels.

Finally, education is offered regarding the patient’s specific health condition(s). Literature is made available, as are referrals to psychological counseling if necessary and/or emotional support groups, if appropriate.

Summary
The human body is a vast network of cells and connective tissue. At the root of all disease, water loss, oxidation and inflammation cause damage and destroy the components that literally hold the body together. Scientific research on connective tissue-rejuvenating therapies is ongoing. We believe that a combination of therapies may improve overall health, offering patients higher resistance to connective tissue damage. Finally, we feel that rather than singular methods, inclusive treatment in accordance with The Water Principle may encourage cellular and connective tissue health and positive life-altering changes, improving lifespan. Moreover, The Water Principle also forms the foundation for larger, more long-term studies on inclusive care methodologies and their correlation with clinically measurable health improvements. 

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Howard Murad, MD, is a board-certified dermatologist, trained pharmacist, founder of the University of Inclusive Health, Associate Clinical Professor of Medicine at UCLA, the man behind Murad, Inc., and best-selling author of The Water Secret. He has treated more than 50,000 patients at his Murad Inclusive Health Medical Group. 

Jeff Murad is the director of program development at the University of Inclusive Health and vice president of product development at Murad, Inc. He oversees product formulation, testing, regulatory compliance and packaging compatibility. He works alongside his father, Howard Murad, MD, on the development of new programs for UIH and new products and formulations, continuing to further the science-based, results-oriented Murad family of products and philosophies.

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