Research Article: Progeria, rapamycin and normal aging: recent breakthrough

Date Published: July 8, 2011

Publisher: Impact Journals LLC

Author(s): Mikhail V. Blagosklonny.



A recent discovery that rapamycin suppresses a pro-senescent phenotype in progeric cells not only suggests a non-toxic therapy for progeria but also implies its similarity with normal aging. For one, rapamycin is also known to suppress aging of regular human cells. Here I discuss four potential scenarios, comparing progeria with both normal and accelerated aging. This reveals further indications of rapamycin both for accelerated aging in obese and for progeria.

Partial Text

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by some features reminiscent of aging, including atherosclerosis and alopecia [3-6]. The median life span is 13 years, and the main cause of death is myocardial infarction and stroke. Progeria is mainly caused by the abnormal accumulation of progerin, a mutant form of the nuclear envelope component lamin A [7, 8]. In cell culture, HGPS cells are prone to replicative senescence (Figure 1) [9-12]. Accumulation of progerin causes nuclear abnormalities, mitotic abnormalities and accelerate telomere shortening. This causes DNA damage response, p53 induction and cell cycle arrest [11, 13-16]. After a number of cell divisions in culture, cells stop proliferating (replicative senescence).

Normal human cells undergo replicative senescence due to telomere shortening, which causes cell cycle arrest [9, 20-22]. But cell cycle arrest is not yet senescence [23, 19]. In the young organism, post-mitotic cells are not senescent. Such cells must undergo geroconversion during lifespan. In cell culture, senescence is characterized by large flat cell morphology (hypertrophy), beta-Gal staining, hyper-secretory phenotype, activated DNA-damage response (even in the absence of DNA damage), resistance to signals (such as insulin), elevated cyclins with inappropriate drive into S-phase, and loss of proliferative potential (PP) [17, 24-42, 17]. Loss of PP, a convenient marker in cell culture, means that the cells cannot resume proliferation even when they are released from arrest, for example, by switching p21 off [2, 43]. Senescent phenotype (including loss of PP) can be linked to hyper-active growth-promoting and nutrient-sensing pathways such as mTOR (Target of Rapamycin). In proliferating cells, growth factors (and nutrients) activate cell mass growth, which is balanced by division. When the cell cycle is arrested, then activated mTOR drives the senescent morphology [2, 17]. Over-activation of the mTOR pathway causes hyper-activation and exhaustion of stem cells too [44-46].

There are at least four models, which are not mutually exclusive

Still, progeria is not accelerated “normal” aging exactly. What is accelerated “normal” aging or accelerated aging, for brevity. If aging is driven by inappropriate activation of nutrient-, hormone- and mitogen-sensing pathways such as mTOR, then nutrients and insulin can accelerate aging. In fact, obesity is associated with all age-related diseases and dramatically shortens life span. This is the accelerated normal aging. As an example, the maximum “years lost life” (YLL) for white men aged 20 to 30 years with a severe level of obesity (BMI >45) is 13 years, representing a 22% reduction in expected remaining life span [111]. As long ago suggested by the Russian endocrinologist Vladimir Dilman, time flies faster in the obese.

Inhibiting farnesylation of progerin by farnesyl transferase inhibitors (FTI) prevents the nuclear blebbing of progeria and has positive effects in animal models [116-122]. Yet, the FTI lonafarnib is a relatively cytotoxic agent with gastrointestinal and hematological dose-limiting toxicities (in cancer patients) [123]. It was shown that insulin-like growth factor 1 extends longevity in a mouse model of human premature aging [124]. However, there is still a long way to clinical applications.





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