Aging
Companies:
Omegal Therapeutics: takes advantage of the organization of genes and regualtory elements into conserved 3D chromatin lopps. There are about 15k of these loops which they call “insualted genomic domains” each of which contains single or multiple genes together with their regulatory elements. The regulatory elements have unique genomic sequences, which makes them attractive therapeutic targets. They have mapped these regulatory elements and created a database of targets, called “EpiZips”. These EpiZips or epigenomic ZIP codes can be targeted by programmable, modular mRNA based epigenomic drugs called “epigenomic controlers”. The epigenomic controllers are delivered into cells using lipid nanopartcile technologies which are translated on the ribosomes into the respective therapeutic proteins. The fusion proteins contain a highy specific DNA binding domain, which is connected through a linker to an epigenomic effector domain that contols gene expression regulators at target insulated genomic domains.
Life Biosciences is inducing cellular rejuvenation through parital epigenetic reprogramming. Starting with a mature injured cell, they are trying to turn back the clock to convert that cell to a more youthfull state, but wihtout going all the way back to a stem cell. Four transcirptions factors (Oct4, Sox2, Klf4 and c-Myc) together can covnert mature cell into an induced pluripotent stem cell. Later it was discovered that c-Myc, an oncogene that can have tetratogenic effects is dispensable for this process.
Introduction:
The ultimate goal of regenerative research is to replace damanged cells in response to injuries and agning. Transdifferentiation (or cell reprogramming), a process thorugh which a mature somatic cell transforms into a new type of mature somatic cell can acheive this gold. In vitro reprogramming of somatic cells has proven to be a powerful too and has allowed the ientificiton of some of the genetic factors required to change identity. The discovery of reverse development in the cridarian Turritopsis dohmii (class Hydrozoa) represents a promising new research system. Faced with unfavorable circumstances, the medusa naturally undergoes cellular reprogramming to revert to a younger life cycle state (the polype) thous avoiding death indefinitely.
Aging is marked by the gradual decline of a multitude of physiological functions leading to an increasing probability of death. Recent work has begun to uncover molecular mechanisms that specify lifespan and to identify alternations in cellular physiology that occur at the end of life. For example, oxidative damage caused by the generation of free radicals in the mitochondria has been found to hasten aging by causing an accumulation of damaged cellular components. The identificaiton of biomarkers for human aging are of key interest to scientists. In this respect, many studies describe genes that provide human age signatures (see US 2007/0161022A1).usaid become reproductively mature, release gamets, and die. medusae of T. dohmii that are stressed, damaged or senescent settle on a surface and transoform into a cyst state that in 24-72 h, metamorphoses back into a single juvenile polyp. By asexual reproduction, the polyp can develop into a large colony (i.e., colonial polyp) that can then release new medusae. Because of its unique life cycle, T. dohmii has been popularized as the “immortal jellyfish”. Aging and lifespan-related genes, serine racemase and MsrA, have been shown to be enriched in the cyst. Supression of serine racemase activity can cause aging-related cognitive dysfunctions in mammals., whereas MsrA has a role in protecting cells from oxidative damages by destroying reactive intermediates or repearing damaged DNA. (Miglietta “Cellular reprogramming and immortality: expression profiling reveals putative genes involved in Turritopsis dohrnii’s life cycle reversal”. Genome Biol. Evol. 13(7). 2021).
Age Related Diseases:
Alzheimer’s disease: Transcriptomic data from microglia in AD conditions reveal an accelerated agining phenotype. It is conceivable that microglial surfveillance response is comproomised with agen, which would lead to a slow accumulation of insults to the CNS potentially leading to neurdegenerative diseases like AD. Genome-Wide Associattion studies from large European and American consortia identified common genetic polymorphisms at loci harboring gnes with microglia-specific epxrewssion pattern in the CNS, such as ABC7, CD33 and members of the MS4A genes cluster as genetic determinatns of AD risk. (Rhinn, “Shifting paradigms: The central role of microglia in Alzheimer’s disease” Neurobiology of Disease 143 (2020))
Obesity: afflict more than 1 in 3 adults in teh US and is responsible for an overall decrease in health and increased risks for cancer, heart disease and neurological deterioration among many others.
Kidney failure and renal fibrosis: are a major concern regarding the aging opulation in the US with ore than 661,000 people either on dialysis or recipients of a kidney transplant. Davidsohn “A single combination gene therapy treats multiple age-related diseases” PNAS, 116 (47) 2019)
Heart Failure: is responsible for 425,000 deaths per year in teh US with a prevalence of over 5.8 million people Davidsohn “A single combination gene therapy treats multiple age-related diseases” PNAS, 116 (47) 2019)
Abnormalities associated with Aging
The gadual deterioration in immune fuction that occurs with aging has been termed immune senescenceThis is manifest both as reduced in vitro immune responsiveness and impaired immune response to vacination and acute infection. The following abnormalities have been associated with aging.
CD8+ T cells which lack CD28: A major feature of immune senescence is the accumulation of clonally expanded memory CD8 T cells characterized by the lack of CD28 expression. The proportion of CD8+ T cells that lack surface expression of CD28 increases with age so that in adulthood, 25-50% of CD8+ T cells are CD28-. In acute viral infections, there is often considerable rapid expansion of CD8+CD28- antiviral effector T cells. Upon antigenic stimulation, these CD8+CD28- T cells produce interferon gamma, but not IL-2 and proliferate poorly.
The phenotype CD57+CD28- T cell subset observed in old age donors may reflect increases in CMV specific CD 8 T cell fequencies. This phenotype has also been reported in other setting such as rheumatoid arthritis and HIV-1 infection.
Abnormalities in CMV positive Elderly:
Polarization towards Effector Memory Cells in CMV elderly: CMV specific CTL have a highly polarized membrane phentoype that is typical of effector memory cells (CD28-, CD57+, CDR7-)
Restricted TCR in CMV sepcific CTL: TCR has shown that CMV specific CTL have highly restricted clonality with greater restriction in the larger expansions. 33% more clonal expansion were observed in CMV seropositive donors compared with negative individuals. These data implicate CMV a major factor in driving oligoclonal expansions in old age. Such an accumulation might impair the ability to respond to heterologous infection and may underlie the negative influcucne of CMV eropositivity on survival in the very elderly.
bcl-2+ CMV specific T cells: It was reproted that CMV specific T cells are uniformly bcl-2+, indicating resistance to apoptosis, which is reminiscent of cells that have reached replicative senescence in cell culture.
Age-associated B cells: have been discovered in mice, which are uniquely responsive to innate stimuli and refractory to CD40 and BCR stimulation. They appear to be generated from mature B cells that exhaustively expand during the inidivual’s lifetime and thus may represent an “exhausted” lymphocyte cell population. Moreover, an IgG- CD27- population, possibly corresponding to exhausted membory B cells acculates in elderly humans. (Hayday 14/368,749)
Epigentic Abnormalities:
Agiging is accompanied by the accuulation of epigenetic changes, such as DNA hypermethylation at promoters.
Epigenome remoding, including widespread changes to DNA methylation adn 3D chromatic structure, is also increasinly recognized as an important mechanism of gene deregulation in cancer.
Abnormalities in Skeletal Muscle:
Ageing is accompanied by decrements in the size and function of skeletal muscle that compromises independence and quality of life in older adults.
–Myosin: Surprisingly, most studies observe that the size and contractile function of fibres expressing slow myosin heavy chain (MHC) I are well-preserved with ageing. In contrast, there are profound age-related decrements in the size and contractile function of the fibres expressing the MHC II isoforms. Notably, lifelong aerobic exercise training is unable to prevent most of the decrements in fast fibre contractile function, which have been implicated as a primary mechanism for the age-related loss in whole-muscle power output. (Sunberg, “Single Muscle Fibre Contractile Function with Ageing” J. Physiol, 600(2023), 20222).
Treatment Strategies:
Gene therapies:
—fibroblast growth factor 21 (FGF21), alpha Kotho, and transforming growth factor-beta1. FGF21 combination therapy:
Davidson “A single combination gene therapy treats multiple age-related diseases” PNAS, 116 (47) 2019) discloses traditional methods largely ignore the relation between age related diseases, narrowly influencing a particular pathway involved in the pathogenesis of a single disease. Targeting gene therapy to a single patholoy cannot correct or prevent the deterioration of health span that results form ultiple age-related diseases. In this respect, they developed and tested 3 AAV based gene therapies and adminsitered them to adult nontransfenic mice for the treatment of 4 age-related diseases. The 3 genes involved were fibroblast growth factor 21 (FGF21), alpha Kotho, and transforming growth factor-beta1. FGF21 has established roles in metabolism and glucose handling, alphaKlotho is a known regulator of intracellular calcium and provides protection in heart and kidney pathologies and TGFbeta1 signaling plays an important role in age related hypertrophic cardiomyopathy, immune recruitment and extracellular matrix formation. Begining with the obesity model, AAV-FgF21 together with either 1 or both of the other 2 gene therapies was able to mitigate the obesity phenotype in a HFD model as well as an aged ND model, although with a slightly diminished (nonsignificant) effect. Proceeding to the type II diabetes model, they observed that all therapeutic combiantions that included AAV-FGF21 rescued the HOMA-IR levels in the treated HFD mice.