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Longevity Research

Research on Modulating Lifespan of Living Cells

This area of our research program is devoted to Dr. McDaniel’s vision to apply and integrate the tools from contemporary molecular biology such as genomics/proteomics/metabolomics with the evaluation of various botanical compounds to modulate the duration of lifespan or to produce a healthier lifespan of living cells.

According to Dr. McDaniel: “I wanted to examine the actual cellular effects of the individual compounds – mixtures of compounds –plant stem cell extracts and the secondary metabolic products of plant stem cell cultures and determine scientifically and with precision how to optimize the concentration, the ratio of compounds, and how to select compounds and ratios to produce the desired clinical effects…that is I wanted to determine and define how to obtain the right ‘dose’ in formulations for topical and systemic use and how to do this cost effectively in high throughput analysis.”

The other part of the vision was to use this methodology to determine how to alter the lifespan of living cells – and by extension tissues, organs and entire organisms – either to extend or shorten their lifespan. The focus for this was intended to be on telomere structure and also mitochondria function.

Additionally a goal was to be able to produce these botanical products in bioreactors so that the variables of culture, climate, cultivar, purity, uniformity, contamination from pesticides, etc. would be removed and a pure pharmaceutical grade production would be possible independent of agricultural issues.

Finally it was a goal to make possible the production of new compounds, different ratios of compounds or more potent concentrations of active compounds using the process of elicitation via manipulating environmental stressors on the biomass within the bioreactor.

The current goals of this research program are:

  1. To modulate (extension or shortening) of lifespan of cell, tissue, organ or organisms by means of modulating telomerase maintenance/repair and/or mitochondrial biogenesis and/or mitochondrial respiratory efficiency.
  2. To define optimal doses and complementary or synergistic combinations and ratios of antioxidants and active compounds for topical and systemic therapies.
  3.  To create undifferentiated biomass or secondary metabolic products from selected plant (or other) materials so that such products can be produced purely, uniformly, and continuously without impact of weather, culture, etc and without contamination by pesticides, fungicides, etc and in an organic, environmentally friendly/green manner of production.
  4. To develop a model for rapid, efficient screening of potential products, plant stem cell extracts and secondary metabolic products of plant stem cell cultures.
  5. To use the biomass as a ‘chemical factory’ use selective elicitation to control the composition of chemicals produced by the biomass as well as produce novel compounds and ratios of compounds not currently available.
  6. Special focus on antioxidants-from nature and synthetic

Research on Healthy Longevity and Lifespan Modulation
(Extension for Healthy Cells and/or Shortening for Unhealthy Cells)

The lifespan of an average cell is primarily determined through the length of telomeres. A telomere is a repetitive sequence of DNA that serves as a “cushion” for chromosomes, and the genetic information they contain, during cell division/replication. Every time a cell divides/replicates, the chromosomes are copied and as a part of that process, the chromosome is shortened. As the cell divides, this shortening process will eventually result in the removal of important data from the chromosome resulting in either the programmed termination of the cell (apoptosis) or aberrant chromosome activity. The telomere, by capping the end of the chromosomes, allows itself to be shortened during the replication process, thereby protecting the chromosomal data. The overall length of the telomere (and the amount of repair/replacement of consumed material that can be performed by the telomere repair mechanism; primarily telomerase reverse transcriptase) determines the number of replications (lifespan) the cell can undergo before apoptosis is needed (through aberrant/damaged chromosomes) or initiated.

By increasing the maintenance/function/repair of the telomeres, it can be expected that the cells will live longer (divide more times).  While this may seem like a positive thing, the issue is far more complicated. For example, a cancer cell is simply a cell that does not undergo programmed apoptosis, but rather replicates itself uncontrollably and as a result of constant replication, mutations in the DNA occur, causing aberrant protein function or even loss of protein production capabilities. This general concept is known as the Hayflick Limit, which basically states that a cell can live a shorter life, free of mutation and in good health, or it can live a longer life with mutations or cancer potential. Obviously solely increasing the lifespan of the cell is a worthy goal; but a more critical goal is the concept of healthy longevity. The goal of healthy longevity is to allow cells to reach their maximum replicative lifespan while maintaining proper cellular function.

If we assume that each cell has a predetermined number of healthy replicative cycles (genetically “encoded” into the cell once the cell is differentiated from a stem cell into a specific cell type) before programmed apoptosis is required, or cellular malfunction occurs; are there environmental or intrinsic factors that would cause the cell to fall short of its maximum healthy lifespan? Unfortunately the answer is yes, and these factors are very common. Some of the factors are:  UV exposure, dietary factors, smoking, and disease. This can be clearly demonstrated in the case of identical twins, who are genetically identical (down to the cellular level), but if one twin smokes and receives excessive UV exposure, this results in a more aged appearance. The environmentally damaged cells may only achieve 60% of their genetically determined healthy lifespan relative to the unexposed twin’s cells. Furthermore, these damaged cells can be important factors in chronic inflammation, cellular/tissue dysfunction resulting in disease states and/or cancer development. The concept of healthy longevity states that these damaged cells can/must be “restored” to maximum potential healthy lifespan levels through improved/efficient telomerase function/repair, increased or more efficient mitochondrial function (elimination of Reactive Oxygen Species {ROS}/Free Radicals), and, when necessary, programmed cell death to protect the organism itself from cellular dysfunction/cancer formation.

The aim of this research is to elucidate and apply discoveries relating to the mechanisms for: optimizing maximum potential lifespan in cells, elimination of cells that are damaged or detrimental to overall lifespan, improving telomere repair and maintenance efficiency, increasing mitochondrial efficiency and protection from ROS induced cellular damage.  In order to achieve this aim, LSE has performed a series of experiments on human cells in culture, as well as wingless fruit flies and began building a library of high antioxidant sterile plant cultures, as well as commercially available extracts for testing purposes.

In one experimental protocol, cultured human skin fibroblasts from a 36 year old and age matched cells from the same subject at 50 years old, were pre-exposed to antioxidants before exposure to UVB radiation and telomerase activity was measured. A summation of these experimental results indicates that antioxidants are capable of boosting telomerase activity in normal and also UVB exposed cells, that antioxidants modulate activity to different degrees (e.g. some are more effective than others at increasing telomerase activity) and that the younger cells may have a higher activity level than the older cells.

Another experiment using a similar protocol was conducted, with the endpoint being analysis of genetic response using microarrays designed by us to examine selected genes responsible for telomerase activity/repair, mitochondrial function, skin health and inflammation. The results of this set of experiments showed some interesting trends:

  1. TERT (telomerase reverse transcriptase, responsible for elongating telomeres following damage/division) levels were significantly reduced in cells of both ages exposed to UVB.
  2. Pre-incubation (for 4hrs or continuously) with various antioxidants prior to UVB light exposure in cells of both ages resulted in a reversal or improvement (increased level) of the suppression of TERT activity caused by UVB exposure.
  3. This pattern was seen in several other genes whose functions relate to DNA repair and inflammatory responses.

TERT Expression Change
(In Human Skin Fibroblasts Exposed to UVB Radiation Following 4hr or Continuous Pre Incubation With The Listed Antioxidant)

TERT Expression (Fold Increase) UVB Only 4hr Green Tea/EGCG Continuous Green Tea/EGCG 4hr Idebenone Continuous Idebenone 4hr Coffee Cherry Extract Continuous Coffee Cherry Extract
36 Year Old Cells -4.6 N/A +1.2 +8.5 +4.4 +8.2 N/A
50 Year Old Cells -7.0 N/A N/A N/A +8.5 +10.1 +9.0

 

Drosophila (fruit fly) populations were then used to study the effect of pretreatment of coffee cherry extract or idebenone (supplemented in their food supply) on overall lifespan. After treatment with the antioxidant for 3 days, the flies were placed on media containing 3% hydrogen peroxide (a known oxidative stressor), and the total lifespan was measured relative to antioxidant niave (no antioxidant treatment) controls. The results of this experiment showed that pre-incubation (ingestion) of coffee cherry extract was most effective at extending the lifespan of the flies in vivo (while, in contrast, idebenone at the concentrations used in this experiment had little effect). An interesting item of note is that the coffee cherry extract demonstrated a greater effect in female flies when compared to male flies (although both groups showed extended longevity).

Fruit Flies Fed Hydrogen Peroxide Nutrient Media
(With or Without Pre-Treatment With Antioxidant Media)

Experimental Condition Average Male Drosophila Lifespan in Days Average Female Drosophila Lifespan in Days Average % Change From Control
Male Female
3% Hydrogen Peroxide Alone 5.7 5.1 N/A N/A
1% Idebenone Pretreatment in 3% Hydrogen Peroxide 5.3 5.5 -7% +9%
1% Coffee Cherry Extract Pretreatment in 3% Hydrogen Peroxide 6.5 7.7 +14% +51%

 

Another aspect of this lifespan research project is the collection of diverse varieties of plants from around the planet and isolation of plant stem cells from various parts of these plants and proliferating these cells in bioreactors (a bioreactor is a small or large scale device/system designed to maintain a biologically active environment; in this case for plant cell/stem cell culture). The biomass produced in the bioreactor or active substances which are released by this biomass as secondary metabolic products  can be used as lifespan modulating agents or used to enhance the mechanisms of healthy longevity.

Plants respond to their environmental stresses by a process called elicitation producing chemicals or compounds which protect them from environmental injury, such as diseases or UV radiation (somewhat analogous to a human’s immune or tanning response).  Plants in controlled culture can have their exposure to these stressors manipulated, so that the plant will produce chemicals in the ratio and quantity needed to provide the benefits desired in this research. These cells may also be genetically modified to alter their activity.

NOTE: This research was sponsored by LifeSpan Extension, LLC a private biotech company.

Learn More/External Links

http://www.lef.org

http://www.nia.nih.gov/

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