Stem Cell Overview–The Future of Regenerative Medicine
The recent scientific breakthroughs that allowed the cloning of mammals from differentiated cells have refuted the old dogma that development is an irreversible process. Modern science has demonstrated that the DNA in an adult nucleus can be reprogrammed into an embryonic state that can direct the complete development of a new organism. Specific regulatory factors in stem cells enhance the regenerative capacity by introducing cellular de-differentiation of adult cells. The activation of quiescent stem cells in adult tissues – from amphibians to humans – provides a pool of
cells for continual maintenance and repair of the postnatal organism after birth. The ultimate goal of regenerative medicine is to extend longevity and quality of life. Studies in a variety of species demonstrate that caloric restriction is the most effective lifestyle change to extend lifespan. Recently, numerous genes have been identified that either enhance or shorter longevity. The challenge for the field of anti-aging medicine is to identify methods to modulate the activity of the most important molecular targets to enhance longevity. Novavit represents an innovative holistic approach to biotechnology using embryonic cells that exemplifies the quote of Hippocrates, “let thy food be thy medicine and let thy medicine be thy food.”
Human Growth Hormone Therapy–The Wrong Target?
The well documented decline in human growth hormone (GH)levels during aging (somatopause) has resulted in the popularity of replacement therapyin anti-aging clinics. Overall, clinical studies of GH therapy in patients with GH deficiency demonstrate the main benefits are increased lean body mass and bone mineral density. Despite these benefits on the quality of life,numerous studies indicate that GH actually decreases longevity in animals and centarians . For example, long-term treatment of obese rats with GH reduced lifespan. Lifelong absence of GH in knockout mice results
in a 20-70% enhanced lifespan that could not be extended further by
caloric restriction. The GH deficient mice exhibit increased insulin sensitivity and glucose homeostasis that promote longevity. The decline of GH during aging in mice has been shown to reduce neoplastic disease, age-related pathologies, and to increase lifespan.
Furthermore, a mutation in the transcription factor Pit-1 decreases GH levels and increases the resistance to oxidative stress enhances the lifespan of mice. Taken together, the studies indicate that GH therapy could have a negative effect on lifespan in humans and that replacement therapy should not exceed the age-related reference range.
The Insulin-Like Growth Factor Longevity Pathway- Klotho
The key conserved pathway (from yeast to humans) that has been shown to regulate lifespan is blockade of insulin-like growth factor 1 (IGF1) signaling(18). In contrast to the negative effects of GH on longevity, several genes in the IGF1 signaling pathway have been recently identified that extend the lifespan of mice. The common functions of these genes relate totheir effects on the caloric restriction pathway controlling insulin sensitivity and the regulation of resistance to oxidative stress. Selective inhibition of the IGF1 signaling pathway will represent a breakthrough in anti-aging
medicine. Recent studies have identified a peptide hormone called klotho that enhances longevity by blocking both IFG1 signaling and inhibiting GH levels . Absence of the klotho gene in mice causes premature aging that increases cardiovascular disease, osteoporosis, skin atrophy, pulmonary emphysema, immune function, and cognitive impairment. Furthermore, polymorphisms in the human klotho gene are associated with decreased lifespan. Increased expression of klotho has been found to extends the lifespan of mice by inhibiting the signaling of insulin and IGF-1 . The klotho hormone has been shown to increase the expression of manganese superoxide dismutase that it turn facilitates removal of reactive oxidative species and confers oxidative stress resistance.
Stem Cells Programmed for Unlimited Longevity –A Factory for Anti-Aging Biomolecules
In contrast to adult cells that utilize GH to stimulate growth, stem cells require klotho, leukemia inhibitory factor, cripto and many other embryonic growth factors. Proteomic studies have identified many unique growth factors and matrix proteins that specifically regulate the growth, metabolism, and signal transduction of embryonic stem cells. For example, cripto, or TDGF1, is an autocrine stem cell growth factor that is required for embryogenesis by stimulating stem cell proliferation at the expense of differentiation.
Recent studies have found that pluripotent stem cells require a set of genes that are not expressed in other cells types. A common subset of at least 92 evolutionarily conserved regulatory genes (e.g. nanog, oct-4, sox-2) provide a unique molecular signature that are responsible for the pluripotent capacity of avian, mouse, and human stem cells . The expression of these genes, together with the absence of differentiation markers, constitutes a signature profile of undifferentiated stem cells irrespective of their species of origin. These genes are involved with extracellular matrix, apoptosis, metabolism and other cellular functions are expressed in avian, murine, and human stem cells.
For example, a recent patent disclosed isolating phospholipids from 6-14 day old chick embryos extended the lifespan of mice. Changes in the composition of phospholipids in the chicken and duck extracts contain alkenyl and acyl groups that are not typically present in later stages of development and were found to extend the live of mice and to reverse several age related dysfunctions in human subjects 47 to 70 years old. Pluripotent stem cells have also been found to express proteoglycans with specific glycoprotein modifications. For example, chondroitin sulphate and dermatan sulphate in early chick embryos express unique proteoglycan modifications that are not expressed in later stages of development. Thus, no single gene is responsible for the undifferentiated state of stems cells. Rather, stem cells are compose d of hundreds to thousands unique bioactive molecules that can effect the function of the adult organism.