Swiss scientists have discovered that knocking out the nuclear receptor corepressor 1 (NCoR1) gene in the muscles of mice allow the animals to run farther, and faster. Knocking out the same gene in fat cells eliminated the problem of diabetes in the mice. And those are only two tissues, of the many types of tissues in a mouse’s body. I wonder if knocking out the NCoR1 gene in human muscles would create a super athlete? Knocking out a particular gene in muscle lets mice run twice as far as normal. Knocking out the same gene in fat cells allows the animals to put on weight without developing type-2 diabetes.

(more…)

(^ Index)
(<– Previous session)

Talks in this session:

1. Choy: Intracellular trafficking and processing of amyloid precursor protein
2. Kown: Age-associated decline in immune function; new role of SIRT1 in regulatory T cells
3. Pan: Regulation of p53 and ageing by SnoN
4. Grueter: Disruption of the lipid synthesis gene, DGAT1, extends longevity

Regina Choy (Berkeley; Shekman lab) — Intracellular trafficking and processing of amyloid precursor protein

The talk began with a review of the proteolytic processing of amyloid precursor protein (APP) into Aß peptides. Choy emphasized that it is important to have a balance between the amyloidogenic and non-amyloidogenic pathways – a bias toward amyloidogenesis places one at risk for Alzheimer’s disease (AD).

The big question: Where is Aß being produced inside the cells? (What are the possible intracellular sites of Aß peptide production? Where is it actually happening). The approach: study of APP trafficking. The goal: Insights into regulation of Aß production and its relationship to AD.

Building on evidence that the primary site of Aß is the endosome, Choy performed RNAi knockdowns of the endosomal sorting machinery (ESCRT complexes as well as the ATPase VPS4). Knockdown of early components in endosomal sorting result in decreased Aß production, but knocking down the later components or VPS4 results in an increase in Aß production. Together with immunofluorescence results, these findings suggest that Aß production happens after APP leaves the early endosome. Surprisingly, however, APP does not colocalize with early endosome markers in the VPS4 knockdown – in fact, it ends up getting rerouted to the TGN. This raises the possibility that Aß production may happen after APP recycles through the TGN.

More beautiful immunofluorescence data followed, bolstering the recycling hypothesis and leading Choy to conclude in favor of a model in which the primary site of Aß production is in the TGN.

Hye-Sook Kown (Gladstone; Ott lab) — Age-associated decline in immune function; new role of SIRT1 in regulatory T cells

Regulatory T cells (Treg) maintain immune tolerance, i.e., they stop the rest of the immune system from attacking the body. They accomplish this by suppressing differentiation of naive cells and the activation of effector cells. This, in turn, helps to prevent autoimmune disease and graft rejection. However, Treg cells increase their activity during aging, which might make elderly people more susceptible to infection.

Treg activity is regulated by FoxP3, which is in turn modified by acetylation that is regulated by SIRT1. Kown used mass spec to identify the specific acetylation sites on FoxP3; she found three, and raising specific antibodies against the acetylated peptides.

Inhibition of SIRT1, a deacetylase, enhances acetylation of FoxP3 at a specific site in both Jurkat T cells and mouse inducible Treg (iTreg) cells. The acetylated protein is stabilized and active, promoting Treg differentiation and survival in a variety of cell culture and in vivo assays.

Thus, by downregulating the activity of Treg cells, SIRT1 promotes a more active immune system: lower iTreg activity promotes increased differentiation of naive T cells and activation of Th1, Th2 and Th17 effector cells. In older people where SIRT1 levels are lower, higher Treg activity may result in a less responsive immune system and higher susceptibility to infection.

In questions, I asked whether SIRT1 inhibition could therefore be used to prevent autoimmune disease – the short answer is “yes”; this has advantages over expanding Treg populations ex vivo, which sometimes results in loss of FoxP3 expression.

Deng Pan (Berkeley; Luo lab) — Regulation of p53 and ageing by SnoN

Starts off with a review of the cancer-aging hypothesis, i.e., the idea that the anticancer activity of tumor suppressors like p53 have a cost: apoptosis and senescence of damaged cells ultimately reduces the regenerative capacity of tissues, contributing to age-related decline in tissue function.

Pan has focused on SnoN, an inhibitor of TGFß/Smad signaling, using a knock-in mouse in which SnoN can no longer bind the Smad promoter. Using this system, he demonstrated that SnoN can function as a tumor suppressor by activating p53-dependent senescence.

SnoN can interact with the PML-p53 pathway; the SnoN protein is a component of PML-nuclear bodies, which in turn activate p53. There are several ways to activate p53: stabilization (i.e., preventing ubiquitination); antiprepression, and promoter-specific activation. How specifically is SnoN activating p53?

Using pulldown assays, Pan showed that SnoN can directly bind to p53, in a manner that does not depend on PML. This binding stabilizes p53, probably because SnoN competes with Mdm2 (which ubiquitinates p53, targeting it for destruction). The working model is that SnoN is a stress transducer that communicates information about cellular stress to the p53 pathway.

The knock-in mice showed premature aging-related phenotypes, including kyphosis and hair loss, as well as higher levels of senescent and apoptotic cells.

Carrie Grueter (Gladstone; Farese lab) — Disruption of the lipid synthesis gene, DGAT1, extends longevity

Given how much we know about fat and lifespan, it is perhaps surprising that very few longevity studies have focused on mice with modified lipid metabolism. To remedy this omission, Carrie Grueter has been studying the effect of the DGAT1 (diacylglycerol O-acyltransferase) knockout on phenotypes including lifespan. (DGAT is involved in triglyceride synthesis.)

Hypothesis: Leanness, with a concomitant improvement in metabolism, will extend longevity.

DGAT-deficient mice use more oxygen than wildtype siblings, but do not consume proportionally more food. The knockout mice are protected from the age-related increase in fat mass, as well as age-related increases in inflammation. (Not surprising since abdominal fat is associated with chronic inflammation.) The knockouts exhibit decreased serum IGF-I levels.

The payoff: DGAT knockouts live 25% longer than wildtype. There’s a cost: according to Grueter’s data, DGAT-KO have trouble lactating and therefore have decreased fecundity. Furthermore, the knockouts are bad at surviving short-term calorie restriction: half the mice fail to survive a 48-hour fast, probably because their core body temperatures plummet in the absence of stored fat to burn – the lethality can be rescued by group-housing the mice with wildtype animals or by raising the temperature to 30°C.

So in sum, the hypothesis enumerated above seems to hold, at least when calories are abundant – but when times are tough, it’s nice to have a little bit of extra padding.

(Next session –>)

Ouroboros

Animal studies support a cancer-promoting role for fat, and in humans, epidemiological data strongly suggest that dietary fat intake may be associated with incidence and mortality of cancers of the breast, colon, rectum, and prostate. There are also data implicating fat in cancers of the ovaries, uterus, pancreas, and lung, but the evidence is not as strong. There is still a debate as to whether it is total dietary fat, specific fats, or total calories that are involved in carcinogenesis. In any event, cancers of breast, colon, and prostate are highest in North America and western Europe and lowest in Asia, and are directly related to the intake of total fat in the diet even when adjusted for total calories. (more…)

” class=”index-image” width=”120″ />

The proportion of elderly at any age without any chronic conditions is small, and disease can trigger a cascade of events resulting in functional deficits and disability. An increase in the number of activities with which an elder has difficulty increases linearly with comorbidity, that is, coexistent medical conditions that further complicate not only the genesis of a functional deficit but also its treatment. For example, rehabilitation for a stroke for an individual who also has painful, degenerative changes in the foot and a low tolerance for stressful activity secondary to angina with exertion would present a particular rehabilitation challenge. Yet, this example encapsulates geriatric rehabilitation specialist’s emphasis on care and function, not cure and disease. (more…)

Weight loss improves many of the adverse health outcomes associated with obesity, including preventing or delaying the onset of diabetes, improving blood sugar control in those with diabetes, reducing low-density lipoprotein (bad cholesterol), raising high-density lipoprotein (good cholesterol), improving hypertension, improving symptoms of osteoarthritis, and providing an improved sense of well-being. (more…)

Activities of Daily Living (ADLs) is the core daily personal care activities that are necessary in order for people to be able to live independently. Loss of mental functioning is measured by other standardized tests and referred to as cognitive impairment. Activities of Daily Livings are particularly important because along with cognitive impairment, and in some cases “medical necessity,” they are the mechanism used by the insurance industry to determine qualification for long-term care benefits and may also be used to determine qualification for admission to a nursing or assisted living home facility. (more…)

The overarching goal of physical therapy rehabilitation is to return the individual to as close to the premorbid level of function as possible or, alternatively, to maximize a person’s current potential for function and maintain it as long as possible. This goal is achieved by promoting changes in the individual, by altering his or her physical health elderly or social environments, or by implementing a combination of both strategies. (more…)

The motility of the gastrointestinal tract is complex, and normal motility is critical to proper secretion and digestion. In order for gastrointestinal motility to be effective, it must be coordinated with other intestinal functions such as secretion and absorption, and it must be regulated and integrated in a precise fashion. (more…)

As people growing older or become elderly, several health risks and health complications and problem may happened because the natural degeneration of human systems and organ. When you are growing older and become member of elderly population, some complications associated with general body aches and pains may occur. (more…)

Growing older results in the various changes in the anatomy and physiology of human cardiovascular system. This affects in both healthy patients and patients with hypertension. The heart gets a less powerful pump, and needs to bring more to do the same job. (more…)