Aging is a complex biological process that involves multiple cellular and molecular mechanisms. As the aging population increases globally, studying the aging process and its associated diseases has become increasingly important. Microphysiological systems (Microphysiological Systems, MPS) are an advanced research tool that can simulate the microenvironment of human organs and tissues, providing a new platform for studying aging.

 Microphysiological system is an in vitro culture system based on microfluidic technology that simulates the function and structure of human organs. It combines cell biology, tissue engineering, and microfabrication techniques to reproduce the three-dimensional structures and physiological functions of tissues at small scales. MPS can be used not only to study the function of healthy organs, but also to simulate disease states and drug screening.

 Aging research has focused on two major areas: age-related phenotypes and age-related diseases (Figure 1). Age-related phenotypes represent features of "normal" aging, including natural changes in various properties, morphology, or structures of the biological system (Figure 1a, Figure 1b). For example, skin wrinkling, poor vision, and circadian disturbances are all included in these common features of aging. Age-related diseases refer to health conditions with higher individual incidence with increasing age (Figure 1c).

Figure 1. Types of aging studies.

(A) Age-related phenotype and age-related diseases.

(B) Examples of age-related changes in cell and tissue levels.

And (C) Age-related organ disease.

1. Study the types of aging phenomena and the microphysiological systems of aging-related diseases

MPS is a cutting-edge technology that uses microchips or microfluidic devices to mimic the function and pathology of human somatic cells, tissues, or organs. These models can be used to better understand complex biological systems and disease mechanisms, as well as to test the efficacy and toxicity of drugs.

 Aging studies at the cellular level:

Through MPS, we can simulate the cellular microenvironment and study the gene expression changes, protein metabolism and cell-cell interactions during cell aging. For example, the functional changes of hepatocytes during aging and their effects on drug metabolism can be studied through liver microphysiological systems.

 Aging studies at the tissue and organ levels:

MPS is able to simulate complex tissues and organs, for example, the heart, lungs, and kidney. Through these systems, the effects of aging on organ function and the associated pathological changes can be studied. For example, cardiac microphysiological systems can be used to study the mechanisms of cardiac aging and cardiovascular disease.

 Studies of cross-organ interaction:

Aging affects not only a single organ, but also the interactions between multiple organs. MPS can study the effect of aging on the overall physiological state by connecting multiple organ chips to simulate the interaction between organs in the human body. For example, through the liver-gut-kidney microphysiological system, it is possible to investigate how drugs change during aging through the metabolic and excretion pathways of different organs during aging.

2. MPS platform design

 Several key parameters, such as geometry, flow conditions, and transport of molecules or drugs, must be considered when designing the MPS. To date, various MPS designs have been developed, each with different geometric features to simulate different tissues or organs.

 Thus, no generic standardized single design is applicable for all MPS models. The MPS size in use usually varies from mm to submicron, with common shapes including circular and rectangular configurations. In general, MPS designs can be classified according to the number of channels or compartments they contain.

Single-channel chips are frequently used for applications and hemodynamic studies involving intravascular blood flow. Dual-channel and multichannel microchips have been used to integrate blood vessels and various tissues. For example, multichannel MPS designs have been created to replicate the blood-brain barrier (BBB), intestine, lung and tumors. Overall, the design of the MPS showed significant variation, depending on the specific study objectives.

3, MPS serves as a model system to study the senescent phenotype of cells, tissues, and organs

 The development of MPS used to mimic the aging phenotype is still in its early stages. Proposed an in vitro 3D tissue microarray model with human senescent fibroblasts and blood vessels to assess how the senescent fibroblasts and the senescent microenvironment influence the behavior of human blood vessels.

 The human brain organoid MPS platform was developed using 3D printing technology to study the dynamics of immune-driven brain aging (Figure 2a), motivated by aging immune cells that can lead to a systemic aging phenotype.

 An in vitro BBB model composed of endothelial cells, pericytes and astrocytes in intermediate (aged) mice can be used to study the occurrence of neurodegenerative diseases (neurodegenerative diseases, NDs) (Figure 2b). The function of the normal and aged BBB model was evaluated by quantification of fluorescein sodium and Evans blualbualbumin. The results show that the permeability coefficient of the aging BBB model is much higher than the standard BBB model.

 The MPS platform contains satellite cells from the donor and its associated skeletal muscle bundles to simulate muscle aging in muscle disease (sarcopenia) and to study contractile differences between young and elderly adult-derived skeletal muscle cells (Figure 2c). The muscle tract has been shown to show different contractile function between the two groups; no synchronous contractions were found in the older sedentary group during electrical stimulation with low hypertrophic potential compared to the younger exercise group.

 In order to summarize the aging of human endothelial cells and study the integrity of the vascular barrier, some researchers have established MPS models using microfluidics to quantify vascular permeability with 70 kDa glucan (Figure 2d). In this study, endothelial cells from older donors (66 years) were cocultured with dermal fibroblasts from young (19 – 34 years) or from older donors (63 – 69 years). The results showed that vascular permeability was more impaired in coculture with old fibroblasts compared to young fibroblasts. The data suggest that greater vascular leakage is accompanied by less vascular integrity in senescent endothelial cells co-cultured with senescent fibroblasts.

Figure 2. Microphysiological systems (MPS) for the aging phenotype.

(A) MPS of immune-driven brain aging.

(B) Blood-brain barrier (BBB) model of in vitro triple co-culture.

(C) Muscle bundles in the microfluidic chip.

(D) microfluidic model of human endothelial cell escence.

4, Limitations and future perspectives of aging research

 The MPS has made significant progress in aging research, but there are still many obstacles and limitations to be addressed and considered (Figure 3).

Figure 3. Challenges of MPS in aging studies.

 Key challenges include the development of vascularization, integration of multiple MPS platforms of various organs and tissues (e. g., human chip systems), procurement of high-quality human cells representing healthy aging / aging states, establishment of standardized protocols, replication of nervous system components, and reproduction of functional properties including mechanical, structural and transport properties.

Despite previously stated limitations, MPS can be a powerful model system for understanding the effects of aging on human physiology and pathology. It overcomes the ethical problems inherent to the animal models. MPS provides a reproducible high-throughput system for simulating aging and human disease, and has the potential to simulate human tissues realistically.

reference documentation:

Seungman Park,Thomas C.Laskow,Jingchun Chen, et al.Microphysiological systems for human aging research.Aging Cell.2024;0 (0):0-0. doi:10.1111/acel.14070