Who doesn’t want to defy age and live longer? Increased longevity has been the focal point of our food, health, and wellness habits. Thanks to enormous efforts in the fields of science and medicine, the global average life expectancy at birth has increased from 48 years in 1950 to 72 years in 2016. Over the last two decades, research goals have been shifting from reducing mortality towards increasing longevity. Scientists have been persistently trying to solve the mystery behind aging and are starting to find concrete answers that hint at potential strategies to increase human lifespans.
What exactly happens when we age?
Aging is a complex process, and thousands of research studies have been conducted to help understand the phenomenon of aging. Aging is characterized by the slowdown of physiological functions and increased susceptibility to diseases. Age-related problems include diabetes, heart diseases, organ dysfunctions, renal failure, osteoporosis (fragile bones), macular degeneration (vision defects), and neurodegenerative diseases, like Alzheimer’s and Parkinson’s.
Scientists have been independently studying different aspects of aging. There are three major mechanisms implicated in aging that have gained much research attention:
- Telomeres and telomerase protein
- Sirtuin proteins
- The Klotho protein
Telomeres and aging:
Telomeres are short sequences of nucleotide repeats found at both ends of each of our chromosomes. Telomere length shortens with each cell division, which contributes to the normal process of cellular aging and sets an upper limit on cell lifetimes. Telomeres provide genomic stability to normal cells and act as a tumor suppression mechanism. Telomere shortening takes place faster in animals that age faster than those that age slowly. The telomerase enzyme synthesizes telomeric DNA and maintains telomere length; in other words, telomerase activity is required to prevent telomere shortening. Telomerase activity is rarely seen in human somatic cells, but is present in germ cells, stem cells, and in 90% of human cancer cells. In cancer cells, telomerase expression leads to uncontrolled proliferation.
Studies of exceptionally long-lived animals have provided insights into the relationship between telomeres and longevity. Among mammals, bats live exceptionally long in comparison to their body size. A recent study published in Science Advances looked at telomere length and telomerase expression in members of the Myotis genus, which holds the record for longest measured lifespan in wild bats of 41 years. Telomere length does not shorten with age in Myotis bats. However, surprisingly, telomerase was not detected in the blood, which suggests that telomere length is maintained by a different mechanism. Five genes were differentially expressed in the Myotis genus as compared to other mammals, hinting at a novel mechanism for telomere maintenance. As cancer incidence in bats is rare, these genes could become excellent targets for future therapies aimed at extending human lifespans.
Sirtuins and aging:
Sirtuins are important proteins for stress resistance and mitochondrial regulation. The Sir genes that encodes sirtuins were first identified in yeast as a regulator of lifespan. In mammals, there are seven sirtuin family members. Researchers have found an interesting link between dietary restrictions, such as fasting, and longevity. Some studies have shown that restricted diet plans and episodic fasting activate mitochondrial sirtuins and slow down aging. The proposed mechanism of action relates to NAD+, which sirtuins require to function. Fasting induces oxidation of NADH to NAD+, and resulting high NAD+ levels activate mitochondrial sirtuins, thus suppressing the formation of reactive oxygen species, which could ultimately lead to reduced aging.
Klotho protein and aging:
The Klotho protein is considered an aging suppressor. It is named after the Greek goddess who spun the thread of life. The Klotho gene was first identified in mice in 1997. Subsequent work has revealed that a mutation in the Klotho gene accelerates aging. Studies in mice have shown that a defect in the gene results in characteristics similar to aging like skin atrophy, arteriosclerosis (thickening of arteries)/cardiovascular disease, infertility, and short life span. Another study has shown that the Klotho protein acts as a circulating hormone, and overexpression of the Klotho gene extends life span. Members of the Klotho gene family act as regulators of endocrine fibroblast growth factors (FGFs), which in turn regulate important metabolic functions. Recent studies have provided a better understanding of how Klotho activates FGF signaling.
Klotho proteins are expressed predominantly in the kidneys, but also in various tissues and organs including adipose (fat) tissue, the brain, liver, pancreas, bladder, skeletal muscle, and the thyroid gland. Studies have shown that Klotho serum levels decrease with age in humans, indicating the role of the protein in aging. Klotho proteins plays a significant role in regulating metabolic functions that lead to age-related diseases. Importantly, they protect cells and tissues from oxidative stress. Klotho deficiency is implicated in a number of diseases including chronic kidney disease, cancer, hypertension, skin atrophy, and diabetes. Klotho gene polymorphisms are associated with osteoporosis, a condition in which bones become weak and brittle, and spondylosis, an age-related degeneration of the spine.
Several studies have shown promising results in the use of Klotho proteins as therapeutic agents to help in slowing down the progression of kidney diseases, diabetes, and cancer.
Conclusions:
A plethora of aging research conducted over the past decades has resulted in the discovery of different mechanisms involved in aging and age-related diseases. The success of aging research will mainly depend on how well it translates from animal models to humans. Ultimately, advances in our understanding of telomeres, sirtuins, and the Klotho proteins, and their roles in the aging process, could reveal novel possibilities for therapies that will allow us to live longer and healthier lives.
If you have any questions or would like to know if we can help you with your innovation challenge, please contact our Life Sciences lead, Jeremy Schmerer at jschmerer@prescouter.com.
