Scientists claim they have turned back biological clocks on aged rat tissues by giving them injections of young blood plasma, creating an effective treatment option for age-related diseases and injuries similar to that provided by fecal transplants.
Research was conducted using heterochronic parabiosis, which involves merging the circulatory systems of two animals of differing ages into one organism’s system – commonly referred to as Hepatochronic Plasma Exchange or HPE 37.
How it works
Scientists are fascinated by the age-defying abilities of naked mole rats, an African rodent that lives underground colonies. This species boasts an astonishing lifespan for such small creatures; scientists are working hard to discover why this incredible feat of longevity exists in nature.
Yuvan Research recently conducted a groundbreaking study showing how plasma treatments made from young pig blood can significantly lower biological age in rats. The treatment more than halved epigenetic clocks of blood, heart, and liver cells as well as improving hypothalamus function – responsible for managing metabolic stress responses within their bodies.
Researchers discovered that cGAS protein was behind rejuvenation effects. This protein regulates cell cycle progression and protects against DNA damage; additionally it is an integral component of anti-ageing processes as it prevents accumulation of harmful free radicals.
Free radicals produced during mitochondrial oxidative phosphorylation can damage cell molecules and lead to cell damage, but luckily a system of endogenous and exogenous antioxidants provides protection from them; however, some free radicals still manage to get past these measures, potentially leading to cell senescence and tissue degeneration.
Recently, scientists from Harvard Medical School and Shanghai’s Tongji University made an incredible discovery: four subtle tweaks to the cGAS gene give naked mole-rats access to an arsenal of genetic tools that enable them to repair DNA damage and fight aging. If successful, these treatments could also reduce disease risks while restoring youthful functions in brain, muscle, and eye tissue.
Biological clocks
Living systems rely on biological clocks to regulate a host of periodic behaviors, including sleep/wake cycles, body temperature regulation, hormone levels and metabolism. Any disturbance to these innate biological rhythms may lead to diseases such as jet lag, depression and bulimia nervosa; moreover aging has been linked with disrupted biological clocks.
At its core, all forms of organisms — from humans and other mammals to fruit flies and worms — share a common mechanism that drives their cells’ aging: “epigenetic” mechanisms which control gene expression at various points during cell development. Reversing them would theoretically reverse aging.
Scientists have long recognized that certain substances can rejuvenate cells and tissues of older animals. For instance, young blood plasma can stimulate regeneration in many organs and tissues of mice and rats; but until now no research had examined whether these effects occur at a molecular level by altering cellular epigenetic clocks.
To address this question, we created and validated six epigenetic clocks (age estimators) based on DNA methylation profiles in rat tissues. Three of the clocks (the pan-tissue, brain, and liver clocks) can be used to estimate age across all tissues/organs while two (rat blood and heart clocks) have been tailored specifically for specific organs/tissues/tissue types/organ types/tissue types (rat pan-tissue clock and rat heart heart clocks).
Our six epigenetic clocks were used to calculate relative age–that is, the ratio of chronological age to maximum lifespan–for both human and rat samples. This method avoided any skewing caused by using one formula for species with vastly differing lifespans; all six rat clocks yielded high-quality estimates with median absolute errors below 0.85 years.
Epigenetic clocks
Epigenetic clocks are mathematically-derived age estimators derived from changes to DNA methylation at particular CpG sites. Epigenetic clocks can be applied across biological samples and tissues in order to estimate age accurately; particularly useful when it comes to measuring relative biological aging rate or “Epigenetic Age Acceleration”, which has been shown to correlate with health states, lifestyle factors and genetic effectors; epidemiological studies have associated EpiAge Acceleration differences with various pathologies or lifestyle factors – suggesting these clocks play an integral role in biological aging processes.
Horvath et al created an epigenetic clock, known as “Horvath’s Clock”, that provides a pan-tissue model combining methylation patterns across different tissues with 27k Illumina array and carefully selected aging changes. The R=0.96 correlation with chronological age shows high accuracy even when considering human and rat tissue (R=0.97 for mixed analyses, or R=0.97 when restricted solely to rat tissues), providing significant compensation against differences in lifespan between species.
Both the Horvath clock and Hannum et al clock demonstrate distinct biological sex differences in their estimates of age; men seeming to experience greater age acceleration than women. Furthermore, longitudinal studies have indicated that both clocks begin slowing as individuals approach death – consistent with biological aging but also showing plateaus in some tissues like heart and liver over time. Yet the discrepancy between chronological and epigenetic age acceleration remains unexplained due to unmeasured genetic or environmental effects.
IgG glycans
IgG Fc antibodies contain sugar chains known as N-glycans that attach directly to their protein backbone, providing IgG with N-glycans that aid its binding with various receptors such as FcgRIIb and Dectin-1 as well as impacting immune response functions. Furthermore, glycosylation of IgG depends on its subclass. IgG3 Fc glycopeptides with O-glycans attached at hinge regions are resistant to endoprotease AspN cleavage while IgG3 Fc glycopeptides without O-glycans are more vulnerable.
Glycans on IgG can have an effect on its stability and half-life. Fab glycans may promote or inhibit IgG’s binding to neonatal Fc receptor (FcRn), increasing or decreasing half-life and impacting antigen-binding capacity of IgG antibodies.
After E5 administration, LC-MS analysis of IgG Fc glycopeptides demonstrated that pro-inflammatory agalactosylated glycan abundance decreased significantly and anti-inflammatory digalactosylated glycan abundance increased significantly; suggesting that changes to these glycans may account for biological age reversal.
These chromatograms were then manually divided into 24 peaks and relative abundances of each directly measured glycan trait determined. Data were normalized to the total area of the chromatogram and then divided further into six groups according to their features.
Chronological age, country of residence and gender were able to explain moderate to substantial portions of variability across all studied glycan traits with the exception of core fucose. Furthermore, caloric restriction was evaluated for its impact on bisecting GlcNAc by measuring IgG glycan levels after two months on a low-calorie diet followed by transfer to one of five more sustainable “maintenance diets”. Although G0 significantly declined after this restriction period ended, its results did not repeat when individuals were restricted to 800kcal/day during that time period.
Results
Plasma fraction treatments significantly decreased the epigenetic age and function of rat blood, heart, and liver tissues, and they improved. This finding is remarkable given that organ decline and oxidative stress contribute to chronic inflammation; rejuvenating effects from pig blood treatments seemed to directly address their inflammation status in rat cells.
Scientists have recently made an astounding discovery: that epigenetic clock can be turned backwards – an essential step to combatting aging. The discovery was made possible by studying Sima, a Sprague Dawley female rat that received blood infusions from younger rats; scientists discovered that she lost 2.5 years off her biological age with this treatment and her immune system also seemed renewed by this approach.
Researchers conducted several analyses on blood indices to try and understand the underlying mechanism, such as bilirubin and serum glutamic-pyruvic transaminase (SGPT) to monitor liver and pancreatic functions; triglycerides, cholesterol, glucose, creatinine and hemoglobin A1C for heart, kidney and hemoglobin monitoring purposes as well as hemoglobin A1C to detect diabetes as well as track blood sugar levels. Plasma fraction treatment caused most indices to move away from values seen among old untreated rats towards those seen among young rats except platelets.
Scientists have unlocked one key component in the remarkable longevity of naked mole-rats. Researchers discovered that their longevity is related to a variant form of DNA repair protein similar to one found mutated in people suffering Alzheimer’s disease; therefore this discovery could provide clues for developing an anti-ageing drug in humans. Their research was published this month in Science journal.
