Factors Responsible for Healthy Aging versus Accelerated Neuromuscular Aging

• Grant number: 24/23570-1
• Support Opportunities: Research Projects - Thematic Grants
• Start date: December 01, 2025
• End date: November 30, 2030
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Mayana Zatz
• Grantee: Mayana Zatz
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• City of the host institution: São Paulo
• Associated researchers: Alberto Augusto Gonçalves de Freitas Castro Ribeiro ; Carlos Frederico Martins Menck ; Guilherme Lopes Yamamoto ; Helder Takashi Imoto Nakaya ; João Paulo Limongi França Guilherme ; Maria Rita dos Santos e Passos Bueno ; Mateus Vidigal de Castro ; Michel Satya Naslavsky ; Tatiana Jazedje da Costa Silva

Abstract

The global population is aging, and understanding the mechanisms responsible for healthy longevity is of great scientific interest. Recent findings have shown that the so-called Blue Zones-regions of the world with the highest longevity-lack reliable data, reinforcing the need to investigate factors that promote healthy aging in genetically diverse populations, such as the Brazilian population. Biological aging leads to complex changes in cellular, tissue, and organ function, response to stimuli, and regenerative capacity, making them more susceptible to dysfunctions. These alterations increase vulnerability to age-related diseases, such as sarcopenia, neurodegeneration, and cognitive decline. However, some individuals reach advanced ages while preserving functionality and health, demonstrating resilience to environmental adversities. Investigating healthy centenarians and nonagenarian's athletes is highly relevant since in these individuals the genetics is much more important than the environment. Conversely, progressive muscular dystrophies (PMDs) accelerate the aging process of skeletal and cardiac muscles, leading to premature death. In Duchenne muscular dystrophy (DMD), the most common form of PMD, patients rarely survive beyond the third decade without intensive care. It is also found that genetic deficiencies in the processing of DNA lesions result in progeroid syndromes, with muscular and neurological degeneration. This study aims to characterize the genomic, molecular, and cellular profiles of long-lived Brazilian individuals who have aged healthily, comparing them to individuals with DMD who have maintained independent ambulation into their third decade-extremely rare cases. Additionally, a subgroup of nonagenarian athletes with high physical performance and recovery capacity will be included as a comparative model to investigate biological adaptations that promote resilience. On the other hand, individuals with progeria or progeroid syndromes will represent the opposite extreme of healthy longevity, allowing the exploration of mechanisms underlying accelerated aging, characterized by early cellular, metabolic, and functional decline. Blood samples will be collected to obtain serum, plasma, peripheral blood mononuclear cells (PBMCs), and genomic DNA. Whole-genome sequencing (WGS), DNA methylation analysis, and quantification of soluble mediators, cytokines, and growth factors in serum and plasma will be performed. To further investigate these mechanisms, induced pluripotent stem cells (iPSCs) will be generated from erythroblasts in selected cases. These iPSCs will be used to create 3D organoids, allowing functional analysis of phenotypes associated with both healthy aging and accelerated neuromuscular aging. The results of this study are expected to reveal mechanisms that confer resilience to aging and neuromuscular degeneration, providing insights for new therapeutic strategies and contributing to a healthier aging process. (AU)