Ageing occurs at different rates for each of us; what remains less clear, however, is how to turn back time–and rejuvenate organs and even the entire body.
Researchers are getting close to making their dream a reality, with a clinical trial set to start later this year which will put partial reprogramming to the test in humans for the first time. But risks exist: push too hard and cells may lose their identity or turn cancerous.
Epigenetic Clocks
An epigenetic clock is a mathematical model that interprets data provided by DNA chips for interpretation of DNA analysis devices, such as bulk tissue samples. These models help determine cell fractions within bulk tissue samples and from this predict the age of each individual cell in them.
Aging is often associated with mutations – permanent changes to DNA sequence. But there are other means by which our DNA can be altered, known as epigenetic modifications that do not change its sequence but instead affect which genes turn on or off; these effects are more stable than mutations and can even be reversed.
Scientists are exploring ways to use these mechanisms to slow or even reverse the aging process and develop drugs to treat age-related diseases. Their goal is to devise a rejuvenation strategy which could enable longer and healthier lives for their target populations.
Epigenetic clocks are one of the key tools in this effort, serving as mathematically derived age estimators based on combinations of methylation patterns and rates at specific CpG sites in DNA. EpiAge, or biological age estimation, is widely used by scientists to gauge cells, tissues and organisms’ biological age versus chronological age (accelerated aging), although any discrepancies may be due to pathologies, health states, lifestyle habits or environmental conditions.
EpiAge can be estimated using various approaches, with DNA methylation serving as its core. Geneticist Steve Horvath designed the original epigenetic clock which uses 353 CpGs with high levels of DNA methylation to calculate EpiAge. Other scientists have developed clocks which evaluate other sets of markers or analyze specific types of cells for accurate estimates.
Numerous multitissue clocks have been evaluated for their ability to accurately predict EpiAge of cells across different tissues and organs. Most recently evaluated is the Skin&blood clock, based on methylation profiles collected from over 50 tissues and cells; its performance outshone previous single-tissue epigenetic clocks or other predictors; however it still produces predictions that deviate from chronological age.
Transcriptional Clocks
Cellular processes leading to aging and disease can be controlled by specific sets of genes that regulate transcriptional clocks in individual cell types; these transcriptional clocks serve as predictive metrics of aging and can be used to gauge rejuvenation interventions’ impact and magnitude.
The original cellular transcriptomic clock to accurately predict age was developed using modular genetic subnetworks inferred from support vector regression using microarray data from 104 individual C. elegans mutants. This model could predict age with 71% accuracy.65 Since then, several studies have refined this approach, such as one using an elastic net model on gene expression data and reaching 82% accuracy; additionally an eigenvalue decomposition algorithm identified 19 genes with high predictive values that were able to accurately predict chronological age from expression levels alone; another study utilized an elastic net model on gene expression data and successfully predicted age with 71% accuracy using single cell transcriptomes from human lung tissue single cell transcriptomes; using single cell expression levels as data.65 These studies all provided accurate estimates of chronological age from their expression levels alone.65
Transcriptional clocks can be constructed from individual cells and have proven useful in predicting the biological age of mice, although they do not yet accurately detect specific age-related disorders. To improve their performance, transcriptional clocks should be trained on multiple biomarkers of aging as well as providing more details on biological processes being measured.
However, individual cell-type aging clocks may differ significantly in terms of trajectory shapes and expression magnitudes (for instance Fcrls and Crlf2 in microglia and Ifi27 in oligodendrocytes); these disparate results often stemming from gene expression variability–also referred to as noise.
Chronological and biological aging clocks trained specifically on individual cell types can better capture these differences than clocks trained on a wide set of gene expression profiles, leading to superior generalization performance.
Researchers recently conducted an innovative study that used transcriptomic data from young and aged mice’ subventricular zones to train transcriptional aging clocks in individual cell types before testing their generalization abilities. These clocks were able to accurately predict the chronological ages of mice with only an average error of 0.06 months – similar to other aging models based on epigenetic markers or DNA methylation. Individual cell-type aging clocks were also able to detect a small rejuvenation effect of exercise on oligodendrocytes and aNSC-NPCs, attributable to changes in gene expression for AC149090.1 and Ifi27 encoding proteins involved with cytokine signaling and response to type I interferon respectively.
Age-Related Diseases
As people live longer, they experience an increasing prevalence of age-related chronic noncommunicable diseases (NCDs). These chronic NCDs include cardiovascular disease, cancers, chronic obstructive pulmonary disease (COPD), type 2 diabetes mellitus (T2DM), osteoarthritis, Alzheimer’s and Parkinson’s diseases and eye disorders that contribute significantly to disability, reduced quality of life and even premature death worldwide. Many factors may contribute to their occurrence such as ageing, genetic predisposition or lifestyle factors affecting different individuals differently; NCDs can include cardiovascular disease, cancers as well.
Researchers are exploring the root causes of age-related diseases to create effective prevention and treatment methods. One approach involves fighting aging at its source at cellular level – leading to rejuvenation of body cells and tissues and therefore reverse many age-related ailments such as vision and hearing loss.
Scientists are conducting studies on the cellular processes responsible for age-related cognitive decline. Experiments utilizing naked mole rats provide opportunities to test new ways of blocking protein aggregate formation that accumulate in brain cells and disrupt their functionality.
Epigenetic clocks rely on chemical tags called methyl groups which change as we age. To calculate an individual’s biological age, scientists employ machine learning techniques that compare DNA methylation patterns at birth with 19 biomarkers that monitor different functions within their bodies; an algorithm then calculates this biological age.
Researchers have demonstrated it is possible to reverse aging in mice through Yamanaka factor genes that convert adult cells to stem cells. Regenerative medicine practices using such stem cells may then help replace damaged ones with fresh new ones and thus reverse aging processes in those areas where regeneration takes place. Scientists have successfully reprogrammed older cells into younger versions themselves in animal models; and are working toward the same goals in human trials.
Progeria syndrome offers another approach to understanding aging; patients begin showing the first symptoms of premature ageing at around 14 and typically show short lifespan, wrinkled skin and stiff joints. While ageing contributes to NCD development in certain individuals, not all do; thus requiring a holistic approach such as diet- and lifestyle modification programs to combat risks related to age-related disease risk reduction.
Rejuvenation
Rejuvenation seeks to restore youthful function to individual cells and tissues at an individual level in order to prevent or treat age-related diseases or disabilities, unlike conventional life extension research which seeks to slow the biological clock that drives aging.
Scientists have identified various markers as causes of aging; rejuvenation biotechnology seeks to directly target them to restore youthful biology in order to prevent or treat age-related diseases.
Rejuvenation begins by preventing the buildup of damaged proteins and other cell debris over time, using molecular medicine techniques to target and repair damage that drives aging.
One of the most promising approaches is short chains of amino acids known as peptides. Peptides act as messengers between cells, controlling hormone production and inflammation control – scientists have even demonstrated how peptides can delay disease in mice!
Other forms of rejuvenation include reversing epigenetic changes by targeting DNA repair genes, lengthening telomeres with gene therapies or clearing harmful senescent cells with senolytic drugs. Combination therapies could provide a holistic approach to human rejuvenation in the future.
Rejuvenation research is rapidly progressing, with companies such as Jeff Bezos-backed Altos Labs and Sam Altman’s Retro Bioscience investing billions into it. Unfortunately, we are still several years away from seeing fully targeted organ or disease specific rejuvenation therapies enter clinical use – conservative estimates place wide available comprehensive rejuvenation at least 10 years away, provided initial therapies succeed in reversing age-related diseases and injuries.
