Stephen Holt, MD

Concepts of Aging

While many seek the “fountain of youth,” no one has found it.  Aging is a complex process which can be modified only by multipronged interventions.  Positive lifestyle is pivotal in the promotion of health and wellbeing.  While one can extol the virtues and benefits of good lifestyle for health maintenance and longevity, the investment in “behavior change today for health tomorrow” is a difficult pathway of intervention. Mental and physical idleness result in loss of vitality. An important promoter of aging is lack of mind or body activity, resulting in the “disuse syndrome,” with its hallmark of premature aging. 

Many theories of aging have been proposed, but no single explanation suffices (Table 1).  Despite uncertainty about aging theories, modern antiaging research has identified several key disorders or processes that promote tissue aging.  These processes include: immune impairment, sleep deprivation, obesity, adverse lifestyle, genetic programming, poor nutrition, hormonal deficiencies or deregulation, inflammation, oxidative stress to tissues, deficient methylation and the formation of glycated proteins (Advanced Glycation End Products, or AGEs). 

A wide range of natural substances have been identified that can provide favorable nutritional or chemical effects on several of these common disorders or processes that accelerate tissue aging. Modern research has identified many natural substances with antiaging properties, but simple interventions or single supplements (or drugs) cannot address efficiently the multifactorial aspects of tissue aging. The intricate, biochemical cascades of events involved in aging require a synergistic approach to the formulation of antiaging substances, specifically dietary supplements.

            The objective of this article is to review and focus on antiaging interventions using dietary supplements, in order to induce youth preserving improvements in body functions and structures.  This compilation of information will permit the natural clinician to adopt a synergistic approach to the correction or retardation of tissue aging using evidence-based, dietary supplement strategies.

Table 1.  Theories and hypotheses of aging with comments about age promoters and putative age eradicators.

Dietary Selections

            The optimal “Antiaging Diet” should be reduced in simple sugars and saturated fat, while being supplemented with omega-3 essential fatty acids (EFA).  The diet should contain modest amounts of protein of mixed origin (vegetable, meat, dairy and fish origin), high in fiber and dense in vital nutrients, such as vitamins, minerals and phytochemicals.  Perhaps the most important dietary adjustments involve the reduction of useless, dietary calories (e.g. simple sugars, saturated fat or alcohol) and a restoration of the balance of omega-3 EFA to omega-6 EFA intake.  The widespread, relative deficiency of omega-3 EFA and imbalance of omega-6:omega-3 dietary intake ratios have been implicated in proinflammatory states, increased risks of cancer or cardiovascular disease risk and the general promotion of chronic disease.

            Omega-3 EFA supplementation is a pivotal step in antiaging, nutrient supplementation, but many fish oil supplements are obsolete.  The amounts of active omega-3 EFA (EPA, eicosapentanoic acid and DHA, docosahexanoic acid) required to achieve disease prevention or therapeutic benefit are much higher than hitherto supposed; and such amounts cannot be administered efficiently in regular fish oil liquids or capsules.  The optimum way to supplement omega-3 EFA is in well tolerated, absorption-enhanced, pure, concentrated forms that are best presented in delayed release, targeted, enteric-coated, capsule delivery systems.  While omega-3 EFA appear of great importance in supplements, the health benefits of omega-9 EFA is apparent in Mediterranean diets that are often enriched with olive oil.

            There are many accounts of the role of mineral enrichment in the diet of certain ethnic groups that enjoy longevity.  Enhanced mineral intake has been proposed as one explanation for the longevity of individuals in Okinawa, Japan and people who live in mountain regions of Pakistan (Hunzas).  These observations form the basis of the putative benefit of holistic concoctions of minerals, trace mineral supplements, coral calcium and cell salt therapies.  While good mineral intake may be important, other dietary or lifestyle factors combine to play a role in the promotion of an extended, healthy lifespan.

Oxidative Tissue Damage

Tissue aging, due to free radical damage, is widely accepted as a tenable theory of aging.  Reactive oxygen species are formed during normal body metabolism and especially during exercise. Many environmental toxins have pro-oxidant effects on tissues.  The body has efficient ways of defending against the propensity to cause tissue damage.  Endogenous antioxidants can “mop up” free radicals.  These antioxidants include superoxide dismutase (SOD), glutathione, catalase, selenium and vitamins A, C and E… to name a few.

Multifunctional, natural antioxidants are ubiquitous in fruit, vegetables and berries.  To provide adequate antioxidant coverage, many physicians are using vitamin supplements (e.g. A, B complex, C, D and E) combined in complex mixtures of berries, greens and vegetable powders. These blended powders contain a vast array of antioxidant phytochemicals and micronutrients.  This complex approach has started to replace the use of multivitamin supplements in the modern practice of Integrative Medicine.  The key to antioxidant supplementation is to attempt to cover all body tissues with an antioxidant blanket of compounds that access many tissues (lipophilic and hydrophilic antioxidants). This approach should use antioxidants with different REDOX potentials, in order to maximize oxygen radical absorbance capacity (ORAC).

Cell membranes are particularly vulnerable to free radical damage.  This circumstance demands the use of lipophilic antioxidants such as turmeric, vitamin E (tocopherols) or essential fatty acids of the omega 3 series (indirect antioxidants).  Particularly valuable common antioxidants include pycnogenol, lutein, lycopene, ellagic acid, alpha lipoic acid, co-enzyme Q10, green tea or coffee polyphenols, bioflavanoids and isoflavones.

Co-enzyme Q10 (ubiquinone) is a powerful antioxidant with well documented benefits in the management of cardiovascular disease (angina, congestive cardiac failure, hypercholesterolemia etc).  This antioxidant may play a role in the management or prevention of macular degeneration, prostate or breast cancer, cognitive decline, Parkinson’s disease, skin aging, muscle weakness and chronic fatigue syndromes.  Idebenone is a modified form of CoQ10 which may have a greater antioxidant action than CoQ10.  

Tissue Glycation

            Glycation or glycosylation results from the undesirable combination of aldehydes, glucose or fructose with proteins.  During cell membrane damage by free radicals, aldehydes, such as malondialdehyde (MDA), are released.  These aldehydes can cross link sugars and proteins, causing protein aggregation with consequential loss of the functional and structural integrity of several tissue proteins.  The linking of proteins with sugars or aldehydes involves a process of carbonylation.  This process of protein linking and aggregation attracts further free radical damage, resulting in the formation of advanced glycation end-products (AGEs).  These AGEs make cellular attachments which induce tissue destruction and the generation of disruptive end-products (e.g. nitric oxide or inflammatory mediators, including tumor necrosis factor (TNF) and undesirable interleukins (IL-6)).

            The generation of AGEs can be interrupted by the use of carnosine that causes “carnosinylation.”  This chemical reaction is protective against the process of carbonylation.  Carnosine can combine with MDA, thereby inhibiting the process of glycation. Glycation results in severe compromise of tissue structure and function in many organs.  The development of AGEs in metabolic syndrome X and diabetes mellitus explains the hallmark presence of premature aging in these disorders.  Glycation is clearly related to the development of atherosclerosis, beta amyloid deposition in the brain (typical of Alzheimer’s disease) and skin aging.  Furthermore, glycation can involve cross linking of sugars or aldehydes with both protein and DNA.  This circumstance impairs the normal genetic functions of DNA.

            Carnosine and its variants (anserine, homocarnosine, N-acetyl carnosine and carcinine) contain alanine and histidine.  Emerging evidence shows the benefit of carnosine in a variety of disorders or illnesses including: states of chronic inflammation, rheumatoid disease, hypertension, vascular thrombosis, peptic ulceration, delayed wound healing, skin aging, radiation induced tissue damage, cancer and cataracts.  Carnosine has well defined antiaging properties by extending the lifespan of laboratory mice; and it has been shown to expand the lifespan of human cell lines grown in tissue cultures (fibroblasts), in several lab experiments.

Methyl Donation (Methylation)

            The maintenance of the structural and functional integrity of several key chemical compounds in the body involves the donation of methyl groups.  Examples of vital compounds that require methylation for optimal function include: high density lipoproteins (HDL), DNA, phospholipods, serotonin and adrenaline.   Without a continuing ability of the body to methylate many pivotal compounds, normal tissue functions cannot proceed.  A common result of impaired methylation is the damaging accumulation of homocysteine. Homocysteine accumulates as a result of its lack of conversion to methionine (a methyl donor).

            Elevated levels of homocysteine are found in states of inflammation and are associated with several diseases, including: cardiovascular disease, dementia, osteoporosis, diabetes mellitus, systemic lupus erythematosis (SLE) and other autoimmune disorders.  These circumstances benefit from the availability of methyl donors such as S-adenosyl methionine (SAMe) or tri-methyl-glycine (TMG), which are present in popular dietary supplements.

            Deregulation of methylation tends to occur with age and exercise increases the need for methyl group donation.  For these reasons aging or over-exercised tissues may suffer protein and DNA damage.  A particular problem occurs with collagen destruction in individuals who over-exercise.  In competitive athletes, tendon, periarticular and ligamentous disruptions result from compromised or sub-optimal methyl donation. Committed or elite athletes may benefit from methyl-donating supplements (TMG and SAMe), to engage in preservation of youthful musculoskeletal function.

Hormonal Deficiency or Imbalance

            There is no evidence to support the naïve notion that hormone deficiencies provide a comprehensive explanation of the aging process.  While specific hormonal deficiency or deregulation contributes to tissue aging in the mature individual, simple hormone replacements with growth hormone (HGH), DHEA, melatonin or sex hormones are not “stand-alone,” antiaging interventions.  That said, hormonal therapies show promising benefits for antiaging when used in the correct context. The relative deficiency of several hormones that occurs with advancing years is perceived by some physicians as a simple opportunity to reverse aging by hormone supplementation. Other physicians perceive reductions in certain hormones as a normal healthy adjustment made by the aging body.  Of course, neither perspective is completely correct and these issues remain debatable among medical practitioners. 

            The administration of human growth hormone (HGH) has become very popular in antiaging medicine, but its use remains controversial.  While a number of studies have shown favorable physical and physiological outcomes with HGH administration, recent metanalysis studies of HGH treatments fail to show acceptable safety and efficacy.  Proponents of growth hormone use in antiaging medicine report muscle mass increase, gastrointestinal benefits, improved visual acuity, enhanced exercise tolerance, blood pressure reductions, improved libido, promotion of immune function and enhanced cognitive activity. Such benefits are undeniable in anecdotal reports, but the duration of some of the recorded benefits of HGH may be limited and the consequences of long term use of HGH in antiaging strategies remain uncertain.

            The observed benefits of growth hormone supplementation must be balanced against known side effects which are most often experienced at high dosages of injected HGH.  Adverse side effects of HGH include soft tissue swelling, entrapment neuropathy, diabetogenic tendencies, gynecomastia, fluid retention, acromegalic features and hepatic enlargement.  The risk of HGH as a promoter of cancer growth is a residual concern.  Notable evidence exists that HGH treatments may enhance risks of colonic cancer.  Claims that HGH can actually accelerate tissue aging remain challenged.  On balance, it is clear that HGH treatments must be carefully planned and monitored by a knowledgeable physician.  The formal prescribing guidelines for HGH use in anti-aging practice remain confusing, but many physicians believe that HGH administration is indicated when mature adults have documented low blood levels of HGH of IGF1.

            Natural ways of boosting HGH release by applying hormonal or nutritional secretagogues are more portable than HGH injections in clinical practice. The classic way of enhancing the secretion of HGH involves the use of growth hormone releasing hormones (e.g. GHRP-6).  Other hormonal secretagogues include GHRH analogues, Ghrelin, ProHGH, with or without GHRH cofactors.  Some growth hormone releasing products are administered by oral capsules or tablets, sublingual or oral sprays, with a variable evidence-base for safety and efficacy.  Growth hormone releasing co-factors include glutamine, combinations of arginine, lysine and ornithine, L-dopa or plant derived mimetics (Mucuna pruriens).  Carnosine, Homeopathic preparations, Gamma hydroxy butyrate (GABA), yeast extracts and mixed mineral supplements.  The use of growth hormone secretagogues over extended periods of time may sometimes result in their ineffectiveness, as the pituitary or its effector mechanisms become tolerant to initial growth hormone releasing actions. 

            De-Hydro-Epi-Androsterone (DHEA) is a hormone that is readily converted to several sex hormones (estrogen, progesterone and testosterone). The decline in the endogenous availability of DHEA with age is associated with several disorders of aging including chronic inflammation, reduction in IGF1, immune impairments, neurodegenerative disorders (e.g. Alzheimers disease) and risks of death in the elderly.  The administration of DHEA in several of these disorders of aging has been reported to produce an overall benefit.  Adverse effects of DHEA administration include severe depression and growth promoting effects of DHEA on the prostate and perhaps other organs.

            While the benefits of DHEA supplementation appear attractive, this supplement should be administered under medical supervision because of its relatively narrow benefit/risk profile.  The combined use of melatonin with DHEA may have added antiaging benefits.  Melatonin is a potent antioxidant hormone which may improve menopausal symptoms, partially restore age-related declines in thyroid function, exert anti-cancer effects and help restore the biorhythm of sleep.  Recent research highlights the potential value of topical melatonin in reversing many changes found in aging skin.

Adaptogenic Herbs and Botanicals

            The term adaptogen is often used in a loose manner in alternative medicine jargon.  Adaptogens are most specifically defined as naturally occurring plant substances that assist in the adaptation of the body to continuing stress.  However, this terminology is restrictive and many natural substances exist that can act as biological response modifiers (BRM) in a favorable way.  The terms adaptogen and BRM may be used interchangeably to advantage.  A large number of nutrients or botanical agents have adaptogenic qualities (Table 2).  Clearly, a good, balanced nutritional intake of vitamins and phytochemicals is pivotal in a comprehensive adaptogenic body status. 

Table 2. Botanical agents that have adaptogenic or biological response modifying effects.  These natural substances can be combined in synergistic formulations to constitute a baseline, natural-antiaging approach.

Calorie Restriction or Calorie Restriction “Mimics”

            Restriction of calorie intake combined with the maintenance of nutrient density of food has powerful antiaging benefits in rodents and probably humans.  Experimental calorie restriction may improve protein metabolism with the elimination of cross-linked protein products by down regulation of “chaperone molecules,” with resulting increases in hepatic protein elimination.  Calorie restriction has been associated with reductions in blood cholesterol, blood markers of inflammation and improvements in glucose tolerance.  Many of these benefits may be related to loss of adipose tissue, but the proposed actions of calorie restriction are legion (Table 3).

-          Lowering of blood pressure

-          Insulin sensitization

-          Reduction of body temperature

-          Apoptosis regulation

-          Decreased oxidative stress

-          Enhanced brain function

-          Stimulation of growth factors

-          Diminished death risk

-          Improved tissue repair

-          Lowering body weight

-          Lowering of blood cholesterol

-          Increased muscle mass

-          Altered hormone profiles

-          Increased energy

-          Anti-stress actions

-          Modulation of protein metabolism

 Table 3.  Proposed or documented effects of calorie restriction on body structures and functions.

            Several natural compounds and drugs have been proposed as agents that can mimic variably the effects of calorie restrictions.  These putative, calorie-restriction mimetics include resveratrol, hydroxycitrate, gymnema alkaloids, alpha lipoic acid, cinnamon (methylhydroxychalones), indoacetate, metformin and thiazolidinediones.  Much interest has focused on the antiaging benefits of resveratrol.  These benefits are potent and versatile.  They include: regulation of apoptosis, antioxidant actions, anticancer effects, cardiovascular benefits and specific gene regulating actions.  The aging gene in question is SIRT1.  This gene modulates tissue aging by inhibiting apoptosis.  Resveratrol exerts complex, poorly understood effects on apoptosis regulation, with an ability to upregulate or downregulate cell death. 

Toxicity and Premature Aging

            The 20th century witnessed the increasing use of synthetic chemicals and the new millennium is a time to experience the adverse effects of these toxins (toxicants).  Toxins are ubiquitous in our environment and the body tissues of animals and humankind.  The association between toxicant exposures derived from food, buildings, or consumer goods and chronic disease is becoming increasingly obvious in contemporary medical research.

            Attempts to avoid or ameliorate exposure to environmental toxins by lifestyle change, consumption of organic vegetables and body cleansing programs are valuable antiaging tactics.  Integrative medicine now stresses the use of non-toxic alternatives to many items that contain health damaging toxins.  Among the undesirable actions of organic chemicals (toxicants) are the promotion of weight gain, propagation of oxidative stress to tissues, direct mutagenic effects and the exertion of unwanted hormonal actions e.g. xenoestrogens.

            While not prominent in antiaging advice, the avoidance of unnecessary pharmaceuticals and hormone replacement therapy (HRT) for menopause appear to be prudent recommendations.  Adverse side effects of medications and iatrogenic drug catastrophes are a major cause of death and premature disability in the US.  Furthermore, the use of conventional sex hormone replacement therapy, with animal estrogens and synthetic progestins, appears to have more risks than benefits in the management of menopause.  The proposed safety of bioidentical hormone treatments remains to be defined, despite the rhetoric.

Immune Function

            Immune senescence is characterized by both deficiencies and deregulation of immune function.  Much interest in natural medicine has focused on the correction of Natural Killer cell function (NK cells), at the expense of considering needs to modulate other components of the aging immune system.  While immune function involves a complex cascade of bio-physiological events, attempts to enhance or modulate immunity, using natural medicines, has often focused inappropriately on the use of single agents of botanical or nutritional origin.

My colleagues and I have tested the hypothesis that complex immune functions are best addressed by synergistic formulations of multiple herbs, botanicals and nutrients.  In vitro and in vivo comparisons of dietary supplements with effects on immune function show that synergistic formulations of substances with known immune modulating effects provide more potent and versatile effects than single or limited compositions of immune stimulating supplements.  This approach is summarized in Table 4 which identifies a combination of natural substances that are associated with specific research. This research shows profound stimulating effects on NK cell activity and cell mediated immunity with associated actions on immune, molecular cascades.  It is noteworthy that complex immune modulating formulations can incorporate botanicals with antiviral properties (e.g. Andrographis paniculata), or extracts of Ecballium elaterium to further enhance immune protection. In brief, evidence has accumulated that improvement in immune function may promote longevity.

• Andrographis paniculata
• Acanthopanax Senticosa
• Green tea
• Turmeric
• Grape seed extract
• Zinc
• Vitamin C
• Ashwagandha
• Oregon grape
• Shiitake mushroom
• Echinacea purpurea
• Goldenseal
• Golden thread
• Aloe Vera
• Garlic
• Astragalus
• Korean ginseng
• Coriolus versicolor
• Active Hexose Correlated Compound (AHCC)
• Beta glucan