Cynthia Kenyon, vice president of aging research at Calico Life Sciences and director of University of California, San Francisco’s Larry L. Hillblom Center for the Biology of Aging,  presented her research regarding evolutionary and molecular processes that can contribute to longevity of a lifespan on April 6 at the Corwin Pavilion as a part of the “Aging in America” lecture series.

Kenyon’s research on longevity first started by observing the chromosomes or genetic material responsible for patterning the body axis in C. elegans. Kenyon first introduced the concept of regulatory genes by describing genes that can be knocked out in fruit flies and whose previous functions could be restored by inserting these genes from C. elegans into fruit flies. In addition, inserting extra copies of regulatory genes into fruit flies could cause the development of extra eyes, spots, wings, legs, etc. 

The rate of aging is established early on in life. In humans, the rate of aging doubles every eight years until around 20 years, at which the rate of aging becomes relatively constant. Kenyon discussed the plasticity of aging by comparing the lifespans of various insects, birds and mammals. For example, a parrot’s lifespan is greater than a canary’s, and a human’s lifespan is greater than a tiger’s. 

Kenyon referenced American scientist Theodosius Dobzhansky’s quote, “Nothing in biology makes sense except in the light of evolution,” to emphasize the significance of evolution of organisms in the development of characteristics such as physical appearance and average lifespan. Although many organisms may share common ancestors, they have evolved to have different lifespans.

The main question which arose from this finding is where the regulatory genes for aging are located. One experiment that was conducted by Kenyon and her lab removed the reproductive organs of C. elegans by laser ablation of the germ cells— a treatment used to heat-destroy targeted cells with an MRI-guided laser probe. The mutated C. elegans were found to be physically younger in their movement after 13 days compared to wild-type or normal C. elegans. 

Kenyon concluded that a key finding from this experiment was that the mutated worms had a less efficient Daf-2 gene. The Daf-2 gene in C. elegans codes for a hormone receptor that is analogous to insulin and IGF-1 receptors in humans. By making the Daf-2 dependent hormone receptors less efficient, cells have increased expression of Daf-16, which is a cellular component that has been linked to activating genes involved in longevity and oxidative stress responses. Oxidative stress can cause cell and tissue damage in the body. 

In other words, Daf-16’s activation to repair stress-affected parts in the body slows down the physiological clock of an organism. Specifically, Daf-16 activates a pathway of recycling or repairment systems through autophagy or the engulfing of useless substances as well as better resistance to xenobiotics, such as chemical or environmental pollutants and toxins. These signaling pathways contribute to extending life span. In a wild-type C. elegans, Daf-16 is more active later in its lifespan.

Kenyon and her colleagues found that worms have a hidden life extension potential that is triggered by a single base pair mutation. In short, lower levels of insulin and IGF-1 signaling caused by the mutation result in a danger signal which activates a protective cellular response that can extend life.

The pathway for potential longevity can be activated by other triggers, such as caloric restriction, mutated or inhibited sensory perception and removing germ cells or the gonads, as mentioned earlier. Although caloric restriction has been shown to increase the lifespan of C. elegans, it is only known that this action provides health benefits in humans. Inhibiting smell or taste in C. elegans increases longevity and involves the Daf-16 transcription factor.

Kenyon mentioned that just as there are triggers that cause longevity, there are triggers that can shorten the lifespan. High levels of Reactive Oxidative Species (ROS), used in common weed killers, are associated with shortened lifespans in C. elegans because of their ability to damage DNA, proteins and lipids in cells. Paraquat, which is a fast-acting herbicide that becomes deactivated in the soil, can generate ROS. Although high exposure to paraquat is associated with reduced life span, low paraquat exposure is shown to help C. elegans live longer, as it partially activates Daf-16 and other stress-responsive transcription factors.

Kenyon continued her presentation with the subject of heterochronic genes that control aging in adults using Daf-16 as well as certain trends related to size and other DNA variations that affect longevity. For example, small dogs have mutated IGF-1 or growth factor genes, and this effect is linked to small dogs being able to live longer than large dogs. 

After discussing the evolution and findings related to longevity, Kenyon presented her lab’s research on protein aggregation and aging in humans. Protein aggregates are common in older animals and are linked to neurodegeneration and found in the oocytes or ovary cells in female C. elegans. 

It was discovered that when a female mates with a male, the age-associated protein aggregates in the oocytes are removed in a span of 30 minutes. The sperm makes a signaling factor that the oocyte senses to cause the degradation of protein aggregate using the cellular garbage disposal site known as the lysosome. In this way, an adult female’s cells can be converted into young embryonic cells and “become immortal,” as Kenyon puts it.

To study aging in humans, computer modeling systems have been developed to predict age using physiological measurements such as strength, blood pressure, reaction time and hormone concentrations. The U.K. Biobank contains 500,000 people’s deeply-phenotyped profiles to map DNA variants and profile what traits vary with age. 

Through mapping DNA variants in the genome-wide association study (GWAS), it was concluded that the top gene category that affected biological age was neuronal excitation. Neuronal excitation is related to the speed and plasticity of neuron networks and further research is being conducted to understand how changes in the nervous system can affect aging because the physiological clock can predict biological age. 

GWAS concluded that increased and decreased levels of aging were best predicted by the level of education and smoking respectively. Other gender-dependent characteristics related to longevity have been ranked using the frailty index for biological age. For example, blood pressure is a stronger indicator of age in females and air expulsion ability is a stronger indicator of age in males.

Related to Kenyon’s discussion of longevity, an upcoming lecture in the “Aging in America Lecture Series” called “Aging Genes and Longevity” will be presented by Malene Hansen on May 23 at 4:30pm in Henley Hall, Room 1010.