The cellular telomere length has been the predictor of life span according to the telomere theory of aging. Telomere is the region of repetitive nucleotide sequences at each end of a chromosome, which protects the end of the chromosome from deterioration/degradation or from fusion with neighboring chromosomes. Telomeres function by preventing genes located near the the ends of chromosomes from degradation. Some of the telomere is lost – telomere shortening occurs during chromosome replication of each cell division. Over time, due to each cell division, the telomere ends become shorter. When the telomere becomes too short, the chromosome reaches a “critical length” and can no longer replicate at which time enzymes that duplicate DNA cannot continue their duplication due to the lack of binding site. If cells divided without telomeres, genes at the ends of chromosomes can not be copied and replicated. The telomeres are disposable buffers blocking the ends of the chromosomes from degradation and are consumed during cell division. The steady shortening of telomeres with each replication in somatic cells account for the phenomenon of cellular senescence i.e. replicative senescence and hayflick limit – the limitation for somatic cells that can divide before replicative senescence – the fact on which the telomere shortening theory of aging is based. Telomere shortening is body’s natural mechanism to prevent genomic instability and uncontrolled cellular proliferation.

There are mechanisms for the maintenance of telomere length either through activated telomerase – a DNA reverse transcriptase which synthesize telomeres or through ALT (Alternative lengthening of telomeres). The exact mechanism of ALT pathway is not known. Telomerase is an enzyme made of protein and RNA subunits that elongates chromosomes by adding TTAGGG sequences to the end of existing chromosomes. Telomerase level is very low, almost undetectable activity in most types of somatic cells except the cells that need to divide regularly (e.g., in the immune system). Shorter telomeres and telomerase inactivation has been one of the causes and mechanisms of aging. Many aging-related diseases are linked to shortened telomeres. A variety of premature aging syndromes are associated with short telomeres. Lengthening the telomeres in certain cells through temporary activation of telomerase (by drugs), or possibly permanently by gene therapy can be the approach for developing life extension drugs.

Telomere-based mechanisms of skin aging and photoaging has been elucidated. Intrinsic aging is largely controlled by progressive telomere shortening, compounded by oxidative damage to telomeres and other cellular constituents. Telomere length of the skin is associated with chronological aging, and may associated with photo aging as well. Comparison of telomere lengths from epidermis samples of varying age revealed that telomere length in the epidermis and in the dermis was reduced with age, and average telomere shortening rates in the epidermis and in the dermis are 9 and 11 bp/yr. Increasing evidence indicates that telomerase plays a significant role in maintenance of skin function and proliferation. Telomerase is active in cells of the epidermis but is almost undetectable in the dermis. Mutations in telomerase component genes in the disease dyskeratosis congenita result in numerous epidermal abnormalities. Studies also indicate that telomerase activity in epidermal stem cells might have roles that go beyond telomere elongation.

Accelerated telomere-shortening and telomerase inactivation has been linked with other aging factors and environmental stress. Oxidative stress, which causes DNA damage, has been shown to hasten the shortening of telomeres in cell culture. Evidence indicates that chronic oxidative stress not only causes progressive damage to cellular membranes, proteins, and molecules, but also induces the slowing down of existing telomerase activity and accelerates telomere shortening. The glutathione (GSH)-dependent system is body’s natural antioxidant system to counteract ROS oxidative stress from cellular respiration. Increasing data suggest the role of the GSH-redox antioxidant system in preserving telomeres from oxidative stress damage. Chronic oxidative stress and reduced glutathione, or compromised GSH-redox system is shown to induce a state of progressive telomere shortening. Telomeres in skin cells may be particularly susceptible to accelerated shortening because of both proliferation and DNA-damaging agents such as reactive oxygen species. In sun exposed skin, UV irradiation also damages DNA and accelerates telomere shortening. Aging and photodamage appear to share a common final telomere initiated signal transduction pathway following disruption of the telomere. These telomere-initiated responses, in combination with UV-induced damage to critical regulatory genes, lead to the photoaging phenotypes.

Vitamin D can slow the shortening of the telomeres. Clinical trials found that vitamin D increases telomerase activity. Data suggest that vitamin D may improve telomere maintenance and prevent cell senescence. Telomerase activators are areas of research for developing topical or oral skin care ingredients that are able to stimulate telomerase activity in the skin cells. TA65 – a telomerase activator- is a proprietary extract of Astragalus root. Astragalus root was already used to stimulate the immune system and wound healing. Saponins in the extract are the chemicals responsible for these activities. Further studies found that these saponins stimulate telomerase activity as well. Clinical trials have established life extension effect of TA-65. In addition, in vivo study revealed the consistent improvement in skin assessments in the product group vs placebo group across multiple measures, suggesting a significant effect of TA-65 on skin although skin assessment by vision score were not based on objective measurements of skin structure and function.