[**overlake.bio**](https://overlake.bio/) is an end-to-end decentralized framework, currently encompassing four scientific projects that look into underexplored aspects of human aging. 

**Problem 1|** Aging has been conceptualized as an increase in intracellular molecular entropy, leading to dysregulation of vital processes, damage accumulation, and consequent deterioration of physiological resilience, resulting in pathology and, ultimately, death. Deleterious alteration of extracellular structural components, i.e., the extracellular matrix, and the damage accumulated therein as a function of time are an emergent hallmark of aging that could have a profound impact on our understanding of the aging process. Presently, there’s a lack of knowledge on how the damage in the extracellular matrix is linked to other, “classical”, hallmarks of aging, such as genomic instability, epigenetic alterations, the loss of proteostasis, etc.   
**Solution 1|** [One of my projects](https://overlake.bio/rakhan/Glycation-of-ribosomes-as-a-driver-of-proteostasis-loss-d8971d87778846349d8f4fc29a91a30b) is dedicated to studying how the increased metabolic flux towards generation of a toxic glycolytic byproduct **methylglyoxal**, arising in response to the damaged extracellular matrix, can result in chemical modification of ribosomes, changing protein synthesis accuracy at the level of mRNA decoding – i.e., how the damaged extracellular matrix, modulating metabolic pathways, can disrupt proteostasis via a novel mechanism: proteins, produced by the faulty ribosomes, contain errors in their amino acid sequences, making them prone to misfold (aberrantly spatially organize), elicit stress responses, and aggregate. This hypothesis won me the [2nd Longevity Prize](https://www.longevityprize.com/prize/hypothesis). I published my initial results as a [preprint](https://dx.doi.org/10.2139/ssrn.4566939) in 2023\.

**Problem 2|** Prominently, age-related damage to the extracellular matrix can exist as sugar- and sugar metabolite-derived chemical adducts and crosslinks, called **advanced glycation end products** (AGEs). Given the slow turnover rate of extracellular proteins and the irreversible nature of AGEs, this form of insult tends to accumulate in the extracellular milieu, disrupting normal tissue homeostasis and promoting intracellular entropic events through various mechanisms, manifested as the hallmarks of aging.   
**Solution 2|** Once formed, AGEs aren’t normally susceptible to repair. One hypothetical way of thwarting or reversing the AGEs accumulation is using engineered biologics, e.g., enzymes designed to act upon glycation intermediates or final adducts/crosslinks, restoring the extracellular matrix to a relatively youthful state. Consequently, [another project of mine](https://overlake.bio/rakhan/Advanced-glycation-end-product-AGE-degrading-enzymes-ce317852187b4639b5e5debe42b62290) aims to create new enzymes that would carry out the task of removing the said noxious chemical modifications, achieving normal homeostasis in aged tissues.

**Problem 3|** Besides the stochastic and purely chemical modifications of the extracellular matrix described above, the latter also changes compositionally, displaying a shift in relative abundance of extracellular proteins and glycans to mirror the cellular physiological state. Although there’s an adequate understanding of what proteins are expressed in the norm, few data exist on what happens with the extracellular matrix composition as humans age.  
**Solution 3|** Each cell type, within the tissue context, expresses a different set of extracellular proteins. I’m working to create [**The Extracellular Matrix Aging Atlas**](https://overlake.bio/rakhan/Extracellular-matrix-aging-atlas-10e0f2ecd2f545afad43fd971cce5be7), a knowledgebase of time-resolved proteomic signatures, derived from published datasets, that would integrate cross-sectional and longitudinal studies scattered across the literature in a comparable and scalable manner. Such a database will serve as a handy tool for looking into compositional dynamics of aging tissues, possibly highlighting common themes across tissues/organs and pinpointing targetable components.

**Problem 4|** Finally, my vision for the longevity research expands and blends into space exploration. I’m convinced that as humanity forays into deep space and attempts to colonize other worlds, it will inevitably face harsh conditions it’s not biologically equipped to withstand: e.g., challenges of microgravity, radiation, unsteady circadian rhythm, isolation.  
**Solution 4|** My [**Spacefarer Phenome**](https://overlake.bio/rakhan/Spacefarer-phenome-6df641ad372c4ac5a64b8a666d30a179) project is the concept for an optimized collection of human phenotypic traits, dictated by genetics, that are specifically adapted for the rigors of space exploration and life in extraterrestrial environments. It encompasses the idea of identifying or engineering these traits to enhance human resilience against space-related challenges, aiming to improve the feasibility and sustainability of long-duration space missions and off-world colonization.