SUMMARY
UCLA researchers in the Department of Pediatrics have developed inhibitors of IGF-1R that can be used to reduce the negative healthspan parameters associated with aging.
BACKGROUND
Human aging results in the continual decline of healthspan parameters spanning organ systems throughout the body. Therefore, therapeutic agents that can reverse or delay the onset of aging-related health decline are of immense interest for clinical applications. Diminished growth hormone (GH) and insulin/insulin-like growth factor-1 receptor (IGF-1R) signaling has been found to extend the lifespan in multiple invivo models including mutations to daf2 in worms, Sch9 in yeast, and Chico in drosophila. Additionally, in multiple follow-up studies, IGF-1 signaling improved mammalian lifespan by improving stress defenses and lowering the risk of proliferative diseases. Recently, functional mutations in the IGF-1R genes were found to be associated with exceptional longevity, resulting in relative IGF-1 resistance. Likewise, in numerous epigenetic studies, higher levels of circulating IGF-1 were found to be associated with multiple site-specific cancers. Thus, this evidence gives credence to the efforts to design therapeutics to modulate IGF-1R signaling with the goal of delaying aging in humans. As a result, much interest has gone towards developing inhibitors and binding proteins with limited deleterious effects, as well as towards expanding our understanding of the mechanism of action more thoroughly.
INNOVATION
Previous studies have shown that longevity arising due to the inhibition of IGF-1 signaling occurred only at conception or in young adulthood as well as low exposure to GH and IGF-1 signaling from early on. UCLA researchers in the Department of Pediatrics have developed a mouse monoclonal antibody (mAb) against the L2 domain of the IGF-1R (L2-Cmu), which selectively interferes with IGF-1 binding to murine IGF-1R, thereby, chronically modulating this pathway in mice. They found that L2-Cmu preferentially improved female healthspan and increased median lifespan by 9% (P = 0.03) in females, along with a reduction in neoplasms and inflammation (P ≤ 0.05). Thus, consistent with other models, targeting IGF-1R signaling appears to be most beneficial to females. Importantly, these effects were achieved at advanced ages i.e., 18-month-old male and female mice
Although, this was a murinized antibody, it is representative of a class of agents that can be further extended for human use. They have also developed antibodies and antibody fragments that bind toIGF-1R thus, blocking normal receptor-ligand interactions and decreasing IGF-1 signaling activity in vivo. The inhibitors can be used to reduce deterioration of health span parameters including those affecting cognitive, cardiac, and motor function, amongst others later in life and upon onset with few deleterious effects. Furthermore, the researchers have developed methodology for producing the novel inhibitors of IGF-1R efficiently for downstream applications.
POTENTIAL APPLICATIONS
- Improve, provide prophylaxis for and/or inhibit deterioration of various healthspan parameters including cardiac health or function, a motor function, body fatness/leanness, muscle strength, exercise endurance, freedom from malignancy and/or inflammation, modulation of biomarkers associated with longevity and general health
- Reversing aging-related disorders and diseases in geriatric patients
ADVANTAGES
- Wide applicability across different species due to the conserved GH and IGF-1 signaling pathway
- Non-invasive treatment for widespread aging-related disorders.
- Improved lifespan in model systems
DEVELOPMENT-TO-DATE
UCLA researchers have developed inhibitors of IGF-1R as well as a protocol for their use in the treatment of declined healthspan associated with aging. The developed inhibitors are murinized antibodies or antibody fragments that are representative of potential application in humans.
Related Papers (from the inventors only)
Mao K, Quipildor GF, Tabrizian T, Novaj A, Guan F, Walters RO, Delahaye F, Hubbard GB, Ikeno Y, Ejima K, Li P, Allison DB, Salimi-Moosavi H, Beltran PJ, Cohen P, Barzilai N, Huffman DM. Late-life targeting of the IGF-1 receptor improves healthspan and lifespan in female mice. Nat Commun. 2018 Jun 19;9(1):2394. doi: 10.1038/s41467-018-04805-5. PMID: 29921922; PMCID: PMC6008442.