Human neurons to model aging: A dish best served old

Abstract

With the advancing age of humans and with it, growing numbers of age-related diseases, aging has become a major focus in recent research. The lack of fitting aging models, especially in neurological diseases where access to human brain samples is limited, has highlighted direct conversion into induced neurons (iN) as an important method to overcome this challenge. Contrary to iPSC reprogramming and its corresponding cell rejuvenation, the generation of iNs enables us to retain aging signatures throughout the conversion process and beyond. In this review, we explore different cell reprogramming methods in light of age-associated neurodegenerative diseases and discuss different approaches, advances, and limitations.

Next‐generation disease modeling with direct conversion: a new path to old neurons

“…We expect such criteria to become more and more popular, extending our knowledge of cell identity, and that they will eventually largely replace classical means of neuronal characterization. The rejuvenation effect of iPSC reprogramming is a major drawback when attempting to model late-onset diseases [17,157,158], and artificial induction of the factor age by overexpressing progerin [151], shortening of telomeres [159], or exposing cells to age-related stressors [12,160] is an upcoming and widely used strategy to elicit a relevant phenotype in iPSC models for neurodegenerative diseases [12,148,[161][162][163]. In vitro generation of patient-specific neurons from iPSCs for modeling diseases of the brain has evolved into an integral part of neuroscience [144][145][146], and employing human iPSC technology to investigate aspects of age-related neurodegenerative diseases in a patient-specific genetic context at a cellular level has yielded important human neuron-specific insights [147][148][149][150].…”

“…In vitro generation of patient-specific neurons from iPSCs for modeling diseases of the brain has evolved into an integral part of neuroscience [144][145][146], and employing human iPSC technology to investigate aspects of age-related neurodegenerative diseases in a patient-specific genetic context at a cellular level has yielded important human neuron-specific insights [147][148][149][150]. 2) [12,17,157]. 2) [10,[151][152][153][154][155][156].…”

“…This boom in applications can be mostly attributed to the explosion of new technologies tailored to iPSC-based systems, most of which are also suitable for directly converted cells. These technologies encompass tools and strategies to harness human donor/patient-specific cells for basic human biology research [9][10][11][12], disease modeling [13][14][15][16][17], drug development and safety [18][19][20][21], or cell replacement strategies [22]. Although on first sight iNs might appear as 'just another way' to generate neurons in the dish, there are important technical and conceptual differences between iPSC-derived neurons and iNs to be noted.…”

“…2) [10,[151][152][153][154][155][156]. The rejuvenation effect of iPSC reprogramming is a major drawback when attempting to model late-onset diseases [17,157,158], and artificial induction of the factor age by overexpressing progerin [151], shortening of telomeres [159], or exposing cells to age-related stressors [12,160] is an upcoming and widely used strategy to elicit a relevant phenotype in iPSC models for neurodegenerative diseases [12,148,[161][162][163]. Direct iN conversion of human fibroblasts from elderly human patients and healthy donors into iNs circumvents this issue and has attracted broad attention.…”

“…Old human donor-derived iNs show stark transcriptomic signatures of aging, as well as nuclear pore and transportassociated aging [10,164], metabolic and mitochondrial aging [9,137], epigenetic aging [137], and other aspects of cellular aging (Fig. 2) [12,17,157]. Human iNs thus stand out as a highly attractive patient-specific model system for age-related neurological diseases and thus significantly extend the possibilities offered by iPSCs.…”