Recognizing the driver and passenger mechanisms of aging

New research on aging explores aging theories from a causal relationship perspective.

For the last few centuries, researchers have been trying to understand the process of aging. Aging results in gradual changes in most body systems, resulting in a decline in physiological functions [1], and it is a phenotypically complex process that is difficult to quantify with a single variable. On the other hand, longevity and lifespan can be quantified and defined. Lifespan is defined as the length of the life of an organism while longevity is how long the organism will live under ideal circumstances. Since aging leads to an exponential increase in mortality, slowing aging will increase longevity and lifespan, so they are often used as a substitute to study aging.

Although several drugs and genetic manipulations have been reported to slow down aging, studies on the mechanistic drivers of aging are relatively few [2]. This is due to the complexity of the biology of aging; however, recent advances in quantitative and phenotypic technologies led to the generation of huge data on age-related changes, and, in turn, resulted in the development of epigenetic clocks that help to quantify aging.

Longevity.Technology: Researchers have also come up with other methods to quantify aging in humans and animals including incidence of aging-related diseases, tissue degeneration and functional assays. However, they are not perfect and their importance in understanding the aging process is still controversial. One more challenge of studying aging is that despite various physiological, cellular and molecular changes accompanying aging, it is difficult to determine whether they are causal or not.

Now a new review in Nature Genetics by renowned biogerontologist João Pedro de Magalhães discusses the causal relationships in biological systems as well as assessing aging theories using animal models and human genetic studies to interpret causality.

What are causal relationships in biology?

It is important to understand the nature of causal relationships before focusing on drivers and passengers of aging. One challenge in determining the causal nature of phenotypes is their potential complexity – casual relationships in biology can be different in nature. The simplest type of causal relationship is where a driver and an outcome have a direct relationship; however, aging and age-related diseases are complex and most often influenced by many genetic and non-genetic factors [2].

Indirect causal relationships involving one or more mediators are quite common in biology. Also, several outcomes are a result of multiple drivers, which can also impact other outcomes leading to inaccurate relationships. Most biological processes and complex diseases include multiple drivers and variables that interact in a non-linear fashion, leading to non-causal relationships. It is also worth highlighting that although phenotypes may have multiple drivers, they can also be driven by a single or a few factors.

Theories of aging

Research indicates that a driver of a phenotype must precede the phenotype and both of them must vary together. Early aging theories focused on hormonal changes since levels of growth hormone and testosterone were reduced with age. However, it is now known that hormonal changes are not drivers of aging – just because they are processes that run parallel to each other does not make one a driver of the other.

With the progress of cellular and molecular biology over the last century, theories of aging involved all crucial cell structures and molecules. Changes in important cellular structures such as telomeres and mitochondria or biological molecules such as DNA and RNA, were thought to be drivers of aging. However, it is not clear that such changes are drivers or passengers of aging [2].

Distinguishing drivers from passengers of aging is a challenging task. This is because the establishment of biological causality in a process like aging which involves multiple organs and slow changes is very difficult. Also, the biological processes of drivers and passengers are highly interconnected, making differentiation difficult.

Although several in vitro studies on the role of reprogramming on rejuvenation exists, the number of in vivo studies is quite limited. Now writing in Trends in Biotechnology
João Pedro de Magalhães PhD is Professor of Molecular Biogerontology at the University of Birmingham

Aging manipulations in model organisms

One important approach in determining causality in biomedical research is studying how manipulations or changes of a variable speculated to be associated with a particular phenotype impact the phenotype. Genetics is more potent in this regard due to its specificity as compared to dietary or pharmacological manipulations. However, it is still difficult to conclude complex genetic diseases and phenotypes that are influenced by several genetic variants along with environmental factors.

Longevity is often used to study aging due to the lack of adequate quantitative measurements concerning aging. However, this is not ideal since longevity can be affected by accidents and non-aging-related diseases. Significant research has taken place in testing specific aging theories in genetically manipulated animal models. Although animal models do not accurately represent human biology, their shorter lifespans and ability to control different variables are advantageous. One of the most important events in testing aging theories in models was the decline or loss of interest in the free radical theory of aging (which proposed aging occurred due to the accumulation of oxidative damage in cells). Below are some of the most popular and well-studied mechanistic theories of aging and their role as a driver or passengers of aging.

Genome integrity in cancer and aging

DNA damage theory of aging is a prevalent theory of aging which states that aging occurs due to the accumulation of DNA damage. Previous studies have indicated that some forms of DNA damage increase with age and disruption of DNA damage response and repair in mice is capable of accelerating aging phenotypes and shortening lifespan. However, evidence is lacking whether preventing the accumulation of DNA damage can slow down aging or not.

Mitochondrial dysfunction

Mitochondrial function has been reported to decline with age in multiple tissues along with accumulation of mitochondrial DNA (mtDNA). Although the role of mitochondria in aging comes from mtDNA mutator mice that display signs of accelerated aging, it is still not proven whether impeding mitochondrial dysfunction impedes aging.

Telomere shortening and telomerase in vitro and in vivo

The fact that telomere shortening led to aging gained popularity 20 years ago when it was found that telomerase elongates telomeres and prevents in vitro replicative senescence in humans. Although telomere shortening has been observed in many aged tissues, in vivo studies have been less supportive of the role of telomere shortening in aging. Knocking out telomerase in mice was found to be only after several generations when the telomere becomes very short. Also, telomerase expansion was observed not to play a role in the drastic increase in mice’s lifespan.

Senescent cells, stem cells and immune cells as possible mediators of aging

The role of senescent cells in aging has been debated for half a century with challenges being that the definition of senescent cell is subjective and several markers are available for senescent cells. Recent research indicates that senescent cells play crucial physiological roles and their elimination is not always of benefit.

Stem cells have also gained attention since their function declines in various tissues with an increase in age. Several studies have shown that disrupting or destroying the function of stem cells can accelerate aging. However, whether retaining stem cell function can delay aging is yet to be proven.

Immune system aging has also been thought to be a major contributor to organismal aging. Chronic low-grade inflammation, also called ‘inflammaging’ is associated with human aging. However, cellular changes should be considered as mediators rather than primary drivers of aging [2].

Protein homeostasis and autophagy

Maintaining protein homeostasis is important, and failure can lead to age-related diseases. Autophagy, which is a process of cell cycling, has been indicated to be important for longevity. Studies on mouse models indicated that inhibition of autophagy led to accelerated aging; however, whether slowing autophagy slowed aging was unclear.

Epigenetics, clocks and aging

Epigenetic clocks which help in the prediction of chronological age and mortality in humans suggest that age-related epigenetic changes can drive the aging process. Although significant epigenetic changes have been observed with aging in several tissues, this could also be passenger aging changes.

Reprogramming of epigenetic clocks indicates that epigenome changes with partial reprogramming can help in cell rejuvenation. However, whether reprogramming can slow down aging in normal animals is yet to be established.

Human genetic studies and causal insights

Genetic association studies along with the discovery of genetic variants associated with a particular disease or phenotype have improved understanding of disease drivers. For example, p53 which is commonly mutated in cancer is assumed to be a common cancer driver. However, determining such associations is difficult in aging [2].

Since human aging cannot be quantified accurately, genetic studies focus on age-related chronic diseases and longevity. However several factors other than aging impact longevity, so determining longevity-associated genes that impact the aging process is not clear.

Additionally, processes considered to be drivers of aging lead to a shorter lifespan and premature pathologies when defective. Human studies also indicate that extrapolating results from animal models to humans is challenging.

Still more work to be done

In conclusion, the study states that the understanding of aging is still incomplete. Research on understanding the drivers of aging has taken a backseat in recent years with focus shifting to longevity, and further studies must take place on understanding the drivers of aging since this can help to shed light on the fundamental process of aging and help to develop therapies that would benefit people worldwide.

[1] https://www.nia.nih.gov/about/budget/biology-aging-3
[2] https://www.nature.com/articles/s41588-023-01627-0